Picolinamides as fungicides

ABSTRACT

This disclosure relates to picolinamides of Formula I and their use as fungicides.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119 of U.S.provisional patent application Ser. No. 62/442914 filed Jan. 5, 2017,which application is hereby incorporated by reference in its entirety.

BACKGROUND & SUMMARY

Fungicides are compounds, of natural or synthetic origin, which act toprotect and/or cure plants against damage caused by agriculturallyrelevant fungi. Generally, no single fungicide is useful in allsituations. Consequently, research is ongoing to produce fungicides thatmay have better performance, are easier to use, and cost less.

The present disclosure relates to picolinamides and their use asfungicides. The compounds of the present disclosure may offer protectionagainst ascomycetes, basidiomycetes, deuteromycetes and oomycetes.

One embodiment of the present disclosure may include compounds ofFormula I:

-   -   wherein:    -   X is hydrogen or C(O)R₅;    -   Y is hydrogen, C(O)R₅, or Q;    -   Q is

-   -   wherein Z is N or N⁺→O⁻ and W is O or S;    -   R₁ is hydrogen or alkyl, substituted with 0,1 or multiple R₈;    -   R₂ is methyl;    -   R₃ and R₃′ are independently chosen from C₂-C₆ alkyl, C₃-C₆        cycloalkyl, aryl or heteroaryl, each optionally substituted with        0, 1 or multiple R₈; Alternatively, R₃ and R₃′ may be taken        together to form a 3-6 membered saturated or partially saturated        carbocycle or heterocycle, optionally substituted with 0, 1 or        multiple R₈;    -   R₄ is chosen from aryl or heteroaryl, each optionally        substituted with 0, 1 or multiple R₈;    -   R₅ is chosen from alkoxy or benzyloxy, each optionally        substituted with 0, 1, or multiple R₈;    -   R₆ is chosen from hydrogen, alkoxy, or halo, each optionally        substituted with 0,1, or multiple R₈;    -   R₇ is chosen from hydrogen, —C(O)R₉, or —CH₂OC(O)R₉;    -   R₈ is chosen from hydrogen, alkyl, aryl, acyl, halo, alkenyl,        alkynyl, alkoxy, cyano, or heterocyclyl, each optionally        substituted with 0, 1, or multiple R₁₀,    -   R₉ is chosen from alkyl, alkoxy, or aryl, each optionally        substituted with 0, 1, or multiple R₈;    -   R₁₀ is chosen from hydrogen, alkyl, aryl, acyl, halo, alkenyl,        alkoxy, or heterocyclyl; and    -   R₁₁ is chosen from hydrogen or alkyl, each substituted with 0, 1        or multiple R₈.

Another embodiment of the present disclosure may include a fungicidalcomposition for the control or prevention of fungal attack comprisingthe compounds described above and a phytologically acceptable carriermaterial.

Yet another embodiment of the present disclosure may include a methodfor the control or prevention of fungal attack on a plant, the methodincluding the steps of applying a fungicidally effective amount of oneor more of the compounds described above to at least one of the fungus,the plant, and an area adjacent to the plant.

It will be understood by those skilled in the art that the followingterms may include generic “R”-groups within their definitions, e.g.,“the term alkoxy refers to an —OR substituent”. It is also understoodthat within the definitions for the following terms, these “R” groupsare included for illustration purposes and should not be construed aslimiting or being limited by substitutions about Formula I.

The term “alkyl” refers to a branched, unbranched, or saturated cycliccarbon chain, including, but not limited to, methyl, ethyl, propyl,butyl, isopropyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term “alkenyl” refers to a branched, unbranched or cyclic carbonchain containing one or more double bonds including, but not limited to,ethenyl, propenyl, butenyl, isopropenyl, isobutenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, and the like.

The terms “aryl” and “Ar” refer to any aromatic ring, mono- orbi-cyclic, containing 0 heteroatoms.

The term “heterocyclyl” refers to any aromatic or non-aromatic ring,mono- or bi-cyclic, containing one or more heteroatoms

The term “alkoxy” refers to an —OR substituent.

The term “acyloxy” refers to an —OC(O)R substituent.

The term “cyano” refers to a —C≡N substituent.

The term “hydroxyl” refers to a —OH substituent.

The term “amino” refers to an —N(R)₂ substituent.

The term “arylalkoxy” refers to —O(CH₂)_(n)Ar where n is an integerselected from the list 1, 2, 3, 4, 5, or 6.

The term “haloalkoxy” refers to an —OR—X substituent, wherein X is Cl,F, Br, or I, or any combination thereof.

The term “haloalkyl” refers to an alkyl, which is substituted with Cl,F, I, or Br or any combination thereof.

The term “halogen” or “halo” refers to one or more halogen atoms,defined as F, Cl, Br, and I.

The term “nitro” refers to a —NO₂ substituent.

The term thioalkyl refers to a —SR substituent.

Throughout the disclosure, reference to the compounds of Formula I isread as also including all stereoisomers, for example diastereomers,enantiomers, and mixtures thereof. In another embodiment, Formula (I) isread as also including salts or hydrates thereof. Exemplary saltsinclude, but are not limited to: hydrochloride, hydrobromide,hydroiodide, trifluoroacetate, and trifluoromethane sulfonate.

It is also understood by those skilled in the art that additionalsubstitution is allowable, unless otherwise noted, as long as the rulesof chemical bonding and strain energy are satisfied and the productstill exhibits fungicidal activity.

Another embodiment of the present disclosure is a use of a compound ofFormula I, for protection of a plant against attack by a phytopathogenicorganism or the treatment of a plant infested by a phytopathogenicorganism, comprising the application of a compound of Formula I, or acomposition comprising the compound to soil, a plant, a part of a plant,foliage, and/or roots.

Additionally, another embodiment of the present disclosure is acomposition useful for protecting a plant against attack by aphytopathogenic organism and/or treatment of a plant infested by aphytopathogenic organism comprising a compound of Formula I and aphytologically acceptable carrier material.

DETAILED DESCRIPTION

The compounds of the present disclosure may be applied by any of avariety of known techniques, either as the compounds or as formulationscomprising the compounds. For example, the compounds may be applied tothe roots or foliage of plants for the control of various fungi, withoutdamaging the commercial value of the plants. The materials may beapplied in the form of any of the generally used formulation types, forexample, as solutions, dusts, wettable powders, flowable concentrate, oremulsifiable concentrates.

Preferably, the compounds of the present disclosure are applied in theform of a formulation, comprising one or more of the compounds ofFormula I with a phytologically acceptable carrier. Concentratedformulations may be dispersed in water, or other liquids, forapplication, or formulations may be dust-like or granular, which maythen be applied without further treatment. The formulations can beprepared according to procedures that are conventional in theagricultural chemical art.

The present disclosure contemplates all vehicles by which one or more ofthe compounds may be formulated for delivery and used as a fungicide.Typically, formulations are applied as aqueous suspensions or emulsions.Such suspensions or emulsions may be produced from water-soluble,water-suspendible, or emulsifiable formulations which are solids,usually known as wettable powders; or liquids, usually known asemulsifiable concentrates, aqueous suspensions, or suspensionconcentrates. As will be readily appreciated, any material to whichthese compounds may be added may be used, provided it yields the desiredutility without significant interference with the activity of thesecompounds as antifungal agents.

Wettable powders, which may be compacted to form water-dispersiblegranules, comprise an intimate mixture of one or more of the compoundsof Formula I, an inert carrier and surfactants. The concentration of thecompound in the wettable powder may be from about 10 percent to about 90percent by weight based on the total weight of the wettable powder, morepreferably about 25 weight percent to about 75 weight percent. In thepreparation of wettable powder formulations, the compounds may becompounded with any finely divided solid, such as prophyllite, talc,chalk, gypsum, Fuller's earth, bentonite, attapulgite, starch, casein,gluten, montmorillonite clays, diatomaceous earths, purified silicatesor the like. In such operations, the finely divided carrier andsurfactants are typically blended with the compound(s) and milled.

Emulsifiable concentrates of the compounds of Formula I may comprise aconvenient concentration, such as from about 1 weight percent to about50 weight percent of the compound, in a suitable liquid, based on thetotal weight of the concentrate. The compounds may be dissolved in aninert carrier, which is either a water-miscible solvent or a mixture ofwater-immiscible organic solvents, and emulsifiers. The concentrates maybe diluted with water and oil to form spray mixtures in the form ofoil-in-water emulsions. Useful organic solvents include aromatics,especially the high-boiling naphthalenic and olefinic portions ofpetroleum such as heavy aromatic naphtha. Other organic solvents mayalso be used, for example, terpenic solvents, including rosinderivatives, aliphatic ketones, such as cyclohexanone, and complexalcohols, such as 2-ethoxyethanol.

Emulsifiers which may be advantageously employed herein may be readilydetermined by those skilled in the art and include various nonionic,anionic, cationic and amphoteric emulsifiers, or a blend of two or moreemulsifiers. Examples of nonionic emulsifiers useful in preparing theemulsifiable concentrates include the polyalkylene glycol ethers andcondensation products of alkyl and aryl phenols, aliphatic alcohols,aliphatic amines or fatty acids with ethylene oxide, propylene oxidessuch as the ethoxylated alkyl phenols and carboxylic esters solubilizedwith the polyol or polyoxyalkylene. Cationic emulsifiers includequaternary ammonium compounds and fatty amine salts. Anionic emulsifiersinclude the oil-soluble salts (e.g., calcium) of alkylaryl sulphonicacids, oil-soluble salts or sulfated polyglycol ethers and appropriatesalts of phosphated polyglycol ether.

Representative organic liquids which may be employed in preparing theemulsifiable concentrates of the compounds of the present disclosure arethe aromatic liquids such as xylene, propyl benzene fractions; or mixednaphthalene fractions, mineral oils, substituted aromatic organicliquids such as dioctyl phthalate; kerosene; dialkyl amides of variousfatty acids, particularly the dimethyl amides of fatty glycols andglycol derivatives such as the n-butyl ether, ethyl ether or methylether of diethylene glycol, the methyl ether of triethylene glycol,petroleum fractions or hydrocarbons such as mineral oil, aromaticsolvents, paraffinic oils, and the like; vegetable oils such as soy beanoil, rape seed oil, olive oil, castor oil, sunflower seed oil, coconutoil, corn oil, cotton seed oil, linseed oil, palm oil, peanut oil,safflower oil, sesame oil, tung oil and the like; esters of the abovevegetable oils; and the like. Mixtures of two or more organic liquidsmay also be employed in the preparation of the emulsifiable concentrate.Organic liquids include xylene, and propyl benzene fractions, withxylene being most preferred in some cases. Surface-active dispersingagents are typically employed in liquid formulations and in an amount offrom 0.1 to 20 percent by weight based on the combined weight of thedispersing agent with one or more of the compounds. The formulations canalso contain other compatible additives, for example, plant growthregulators and other biologically active compounds used in agriculture.

Aqueous suspensions comprise suspensions of one or more water-insolublecompounds of Formula I, dispersed in an aqueous vehicle at aconcentration in the range from about 1 to about 50 weight percent,based on the total weight of the aqueous suspension. Suspensions areprepared by finely grinding one or more of the compounds, and vigorouslymixing the ground material into a vehicle comprised of water andsurfactants chosen from the same types discussed above. Othercomponents, such as inorganic salts and synthetic or natural gums, mayalso be added to increase the density and viscosity of the aqueousvehicle.

The compounds of Formula I can also be applied as granular formulations,which are particularly useful for applications to the soil. Granularformulations generally contain from about 0.5 to about 10 weightpercent, based on the total weight of the granular formulation of thecompound(s), dispersed in an inert carrier which consists entirely or inlarge part of coarsely divided inert material such as attapulgite,bentonite, diatomite, clay or a similar inexpensive substance. Suchformulations are usually prepared by dissolving the compounds in asuitable solvent and applying it to a granular carrier which has beenpreformed to the appropriate particle size, in the range of from about0.5 to about 3 mm. A suitable solvent is a solvent in which the compoundis substantially or completely soluble. Such formulations may also beprepared by making a dough or paste of the carrier and the compound andsolvent, and crushing and drying to obtain the desired granularparticle.

Dusts containing the compounds of Formula I may be prepared byintimately mixing one or more of the compounds in powdered form with asuitable dusty agricultural carrier, such as, for example, kaolin clay,ground volcanic rock, and the like. Dusts can suitably contain fromabout 1 to about 10 weight percent of the compounds, based on the totalweight of the dust.

The formulations may additionally contain adjuvant surfactants toenhance deposition, wetting, and penetration of the compounds onto thetarget crop and organism. These adjuvant surfactants may optionally beemployed as a component of the formulation or as a tank mix. The amountof adjuvant surfactant will typically vary from 0.01 to 1.0 percent byvolume, based on a spray-volume of water, preferably 0.05 to 0.5 volumepercent. Suitable adjuvant surfactants include, but are not limited toethoxylated nonyl phenols, ethoxylated synthetic or natural alcohols,salts of the esters or sulphosuccinic acids, ethoxylatedorganosilicones, ethoxylated fatty amines, blends of surfactants withmineral or vegetable oils, crop oil concentrate (mineral oil(85%)+emulsifiers (15%)); nonylphenol ethoxylate;benzylcocoalkyldimethyl quaternary ammonium salt; blend of petroleumhydrocarbon, alkyl esters, organic acid, and anionic surfactant; C₉-C₁₁alkylpolyglycoside; phosphated alcohol ethoxylate; natural primaryalcohol (C₁₂-C₁₆) ethoxylate; di-sec-butylphenol EO-PO block copolymer;polysiloxane-methyl cap; nonylphenol ethoxylate+urea ammonium nitrrate;emulsified methylated seed oil; tridecyl alcohol (synthetic) ethoxylate(8EO); tallow amine ethoxylate (15 EO); PEG(400) dioleate-99. Theformulations may also include oil-in-water emulsions such as thosedisclosed in U.S. patent application Ser. No. 11/495,228, the disclosureof which is expressly incorporated by reference herein.

The formulations may optionally include combinations that contain otherpesticidal compounds. Such additional pesticidal compounds may befungicides, insecticides, herbicides, nematocides, miticides,arthropodicides, bactericides or combinations thereof that arecompatible with the compounds of the present disclosure in the mediumselected for application, and not antagonistic to the activity of thepresent compounds. Accordingly, in such embodiments, the otherpesticidal compound is employed as a supplemental toxicant for the sameor for a different pesticidal use. The compounds of Formula I and thepesticidal compound in the combination can generally be present in aweight ratio of from 1:100 to100:1.

The compounds of the present disclosure may also be combined with otherfungicides to form fungicidal mixtures and synergistic mixtures thereof.The fungicidal compounds of the present disclosure are often applied inconjunction with one or more other fungicides to control a wider varietyof undesirable diseases. When used in conjunction with otherfungicide(s), the presently claimed compounds may be formulated with theother fungicide(s), tank-mixed with the other fungicide(s) or appliedsequentially with the other fungicide(s). Such other fungicides mayinclude 2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol,8-hydroxyquinoline sulfate, ametoctradin, amisulbrom, antimycin,Ampelomyces quisqualis, azaconazole, Bacillus subtilis, Bacillussubtilis strain QST713, benalaxyl, benomyl, benthiavalicarb-isopropyl,benzovindiflupyr, benzylaminobenzene-sulfonate (BABS) salt,bicarbonates, biphenyl, bismerthiazol, bitertanol, bixafen,blasticidin-S, borax, Bordeaux mixture, boscalid, bromuconazole,bupirimate, calcium polysulfide, captafol, captan, carbendazim,carboxin, carpropamid, carvone, chlazafenone, chloroneb, chlorothalonil,chlozolinate, Coniothyrium minitans, copper hydroxide, copper octanoate,copper oxychloride, copper sulfate, copper sulfate (tribasic), cuprousoxide, cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil,dazomet, debacarb, diammonium ethylenebis-(dithiocarbamate),dichlofluanid, dichlorophen, diclocymet, diclomezine, dichloran,diethofencarb, difenoconazole, difenzoquat ion, diflumetorim,dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinobuton,dinocap, diphenylamine, dithianon, dodemorph, dodemorph acetate, dodine,dodine free base, edifenphos, enestrobin, enestroburin, epoxiconazole,ethaboxam, ethoxyquin, etridiazole, famoxadone, fenamidone, fenarimol,fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil,fenpropidin, fenpropimorph, fenpyrazamine, fentin, fentin acetate,fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, fluindapyr,flumorph, fluopicolide, fluopyram, fluoroimide, fluoxastrobin,fluquinconazole, flusilazole, flusulfamide, flutianil, flutolanil,flutriafol, fluxapyroxad, folpet, formaldehyde, fosetyl,fosetyl-aluminium, fuberidazole, furalaxyl, furametpyr, guazatine,guazatine acetates, GY-81, hexachlorobenzene, hexaconazole, hymexazol,imazalil, imazalil sulfate, imibenconazole, iminoctadine, iminoctadinetriacetate, iminoctadine tris(albesilate), iodocarb, ipconazole,ipfenpyrazolone, iprobenfos, iprodione, iprovalicarb, isofetamide,isoprothiolane, isopyrazam, isotianil, kasugamycin, kasugamycinhydrochloride hydrate, kresoxium-methyl, laminarin, mancopper, mancozeb,mandipropamid, maneb, mefenoxam, mepanipyrim, mepronil, meptyl-dinocap,mercuric chloride, mercuric oxide, mercurous chloride, metalaxyl,metalaxyl-M, metam, metam-ammonium, metam-potassium, metam-sodium,metconazole, methasulfocarb, methyl iodide, methyl isothiocyanate,metiram, metominostrobin, metrafenone, mildiomycin, myclobutanil, nabam,nitrothal-isopropyl, nuarimol, octhilinone, ofurace, oleic acid (fattyacids), orysastrobin, oxadixyl, oxathiapiprolin, oxine-copper,oxpoconazole fumarate, oxycarboxin, pefurazoate, penconazole,pencycuron, penflufen, pentachlorophenol, pentachlorophenyl laurate,penthiopyrad, phenylmercury acetate, phosphonic acid, phthalide,picoxystrobin, polyoxin B, polyoxins, polyoxorim, potassium bicarbonate,potassium hydroxyquinoline sulfate, probenazole, prochloraz,procymidone, propamocarb, propamocarb hydrochloride, propiconazole,propineb, proquinazid, prothioconazole, pydiflumetofen, pyrametostrobin,pyraoxystrobin, pyraclostrobin, pyraziflumid, pyrazophos, pyribencarb,pyributicarb, pyrifenox, pyrimethanil, pyriofenone, pyroquilon,quinoclamine, quinoxyfen, quintozene, Reynoutria sachalinensis extract,sedaxane, silthiofam, simeconazole, sodium 2-phenylphenoxide, sodiumbicarbonate, sodium pentachlorophenoxide, spiroxamine, sulfur, SYP-Z048,tar oils, tebuconazole, tebufloquin, tecnazene, tetraconazole,thiabendazole, thifluzamide, thiophanate-methyl, thiram, tiadinil,tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, triazoxide,tricyclazole, tridemorph, trifloxystrobin, triflumizole, triforine,triticonazole, validamycin, valifenalate, valiphenal, vinclozolin,zineb, ziram, zoxamide, Candida oleophila, Fusarium oxysporum,Gliocladium spp., Phlebiopsis gigantea, Streptomyces griseoviridis,Trichoderma spp.,(RS)-N-(3,5-dichlorophenyl)-2-(methoxymethyl)-succinimide,1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone hydrate,1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane,2-(2-heptadecyl-2-imidazolin-1-yl)ethanol,2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4,4-tetraoxide,2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride,2-methoxyethylmercury silicate, 3-(4-chlorophenyl)-5-methylrhodanine,4-(2-nitroprop-1-enyl)phenyl thiocyanateme, ampropylfos, anilazine,azithiram, barium polysulfide, Bayer 32394, benodanil, benquinox,bentaluron, benzamacril; benzamacril-isobutyl, benzamorf, binapacryl,bis(methylmercury) sulfate, bis(tributyltin) oxide, buthiobate, cadmiumcalcium copper zinc chromate sulfate, carbamorph, CECA, chlobenthiazone,chloraniformethan, chlorfenazole, chlorquinox, climbazole, copperbis(3-phenylsalicylate), copper zinc chromate, coumoxystrobin, cufraneb,cupric hydrazinium sulfate, cuprobam, cyclafuramid, cypendazole,cyprofuram, decafentin, dichlobentiazox, dichlone, dichlozoline,diclobutrazol, dimethirimol, dinocton, dinosulfon, dinoterbon,dipymetitrone, dipyrithione, ditalimfos, dodicin, drazoxolon, EBP,enoxastrobin, ESBP, etaconazole, etem, ethirim, fenaminstrobin,fenaminosulf, fenapanil, fenitropan, fenpicoxamid, flufenoxystrobin,fluotrimazole, furcarbanil, furconazole, furconazole-cis, furmecyclox,furophanate, glyodine, griseofulvin, halacrinate, Hercules 3944,hexylthiofos, ICIA0858, ipfentrifluconazole, isopamphos, isovaledione,mandestrobin, mebenil, mecarbinzid, mefentrifluconazole, metazoxolon,methfuroxam, methylmercury dicyandiamide, metsulfovax, milneb,mucochloric anhydride, myclozolin, N-3,5-dichlorophenyl-succinimide,N-3-nitrophenylitaconimide, natamycin,N-ethylmercurio-4-toluenesulfonanilide, nickelbis(dimethyldithiocarbamate), OCH, phenylmercurydimethyldithiocarbamate, phenylmercury nitrate, phosdiphen, prothiocarb;prothiocarb hydrochloride, pyracarbolid, pyridinitril, pyrisoxazole,pyroxychlor, pyroxyfur, quinacetol; quinacetol sulfate, quinazamid,quinconazole, quinofumelin, rabenzazole, salicylanilide, SSF-109,sultropen, tecoram, thiadifluor, thicyofen, thiochlorfenphim,thiophanate, thioquinox, tioxymid, triamiphos, triarimol, triazbutil,trichlamide, triclopyricarb, triflumezopyrim, urbacid, zarilamid, andany combinations thereof.

Additionally, the compounds described herein may be combined with otherpesticides, including insecticides, nematocides, miticides,arthropodicides, bactericides or combinations thereof that arecompatible with the compounds of the present disclosure in the mediumselected for application, and not antagonistic to the activity of thepresent compounds to form pesticidal mixtures and synergistic mixturesthereof. The fungicidal compounds of the present disclosure may beapplied in conjunction with one or more other pesticides to control awider variety of undesirable pests. When used in conjunction with otherpesticides, the presently claimed compounds may be formulated with theother pesticide(s), tank-mixed with the other pesticide(s) or appliedsequentially with the other pesticide(s). Typical insecticides include,but are not limited to: 1,2-dichloropropane, abamectin, acephate,acetamiprid, acethion, acetoprole, acrinathrin, acrylonitrile,alanycarb, aldicarb, aldoxycarb, aldrin, allethrin, allosamidin,allyxycarb, alpha-cypermethrin, alpha-ecdysone, alpha-endosulfan,amidithion, aminocarb, amiton, amiton oxalate, amitraz, anabasine,athidathion, azadirachtin, azamethiphos, azinphos-ethyl,azinphos-methyl, azothoate, barium hexafluorosilicate, barthrin,bendiocarb, benfuracarb, bensultap, beta-cyfluthrin, beta-cypermethrin,bifenthrin, bioallethrin, bioethanomethrin, biopermethrin, bistrifluron,borax, boric acid, bromfenvinfos, bromocyclen, bromo-DDT, bromophos,bromophos-ethyl, bufencarb, buprofezin, butacarb, butathiofos,butocarboxim, butonate, butoxycarboxim, cadusafos, calcium arsenate,calcium polysulfide, camphechlor, carbanolate, carbaryl, carbofuran,carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan,cartap, cartap hydrochloride, chlorantraniliprole, chlorbicyclen,chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride,chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chlorfluazuron,chlormephos, chloroform, chloropicrin, chlorphoxim, chlorprazophos,chlorpyrifos, chlorpyrifos-methyl, chlorthiophos, chromafenozide,cinerin I, cinerin II, cinerins, cismethrin, cloethocarb, closantel,clothianidin, copper acetoarsenite, copper arsenate, copper naphthenate,copper oleate, coumaphos, coumithoate, crotamiton, crotoxyphos,crufomate, cryolite, cyanofenphos, cyanophos, cyanthoate,cyantraniliprole, cyclethrin, cycloprothrin, cyfluthrin, cyhalothrin,cypermethrin, cyphenothrin, cyromazine, cythioate, DDT, decarbofuran,deltamethrin, demephion, demephion-O, demephion-S, demeton,demeton-methyl, demeton-O, demeton-O-methyl, demeton-S,demeton-S-methyl, demeton-S-methylsulphon, diafenthiuron, dialifos,diatomaceous earth, diazinon, dicapthon, dichlofenthion, dichlorvos,dicresyl, dicrotophos, dicyclanil, dieldrin, diflubenzuron, dilor,dimefluthrin, dimefox, dimetan, dimethoate, dimethrin, dimethylvinphos,dimetilan, dinex, dinex-diclexine, dinoprop, dinosam, dinotefuran,diofenolan, dioxabenzofos, dioxacarb, dioxathion, disulfoton,dithicrofos, d-limonene, DNOC, DNOC-ammonium, DNOC-potassium,DNOC-sodium, doramectin, ecdysterone, emamectin, emamectin benzoate,EMPC, empenthrin, endosulfan, endothion, endrin, EPN, epofenonane,eprinomectin, esdepalléthrine, esfenvalerate, etaphos, ethiofencarb,ethion, ethiprole, ethoate-methyl, ethoprophos, ethyl formate,ethyl-DDD, ethylene dibromide, ethylene dichloride, ethylene oxide,etofenprox, etrimfos, EXD, famphur, fenamiphos, fenazaflor,fenchlorphos, fenethacarb, fenfluthrin, fenitrothion, fenobucarb,fenoxacrim, fenoxycarb, fenpirithrin, fenpropathrin, fensulfothion,fenthion, fenthion-ethyl, fenvalerate, fipronil, flonicamid,flubendiamide, flucofuron, flucycloxuron, flucythrinate, flufenerim,flufenoxuron, flufenprox, fluvalinate, fonofos, formetanate, formetanatehydrochloride, formothion, formparanate, formparanate hydrochloride,fosmethilan, fospirate, fosthietan, furathiocarb, furethrin,gamma-cyhalothrin, gamma-HCH, halfenprox, halofenozide, HCH, HEOD,heptachlor, heptenophos, heterophos, hexaflumuron, HHDN, hydramethylnon,hydrogen cyanide, hydroprene, hyquincarb, imidacloprid, imiprothrin,indoxacarb, iodomethane, IPSP, isazofos, isobenzan, isocarbophos,isodrin, isofenphos, isofenphos-methyl, isoprocarb, isoprothiolane,isothioate, isoxathion, ivermectin, jasmolin I, jasmolin II, jodfenphos,juvenile hormone I, juvenile hormone II, juvenile hormone III, kelevan,kinoprene, lambda-cyhalothrin, lead arsenate, lepimectin, leptophos,lindane, lirimfos, lufenuron, lythidathion, malathion, malonoben,mazidox, mecarbam, mecarphon, menazon, mephosfolan, mercurous chloride,mesulfenfos, metaflumizone, methacrifos, methamidophos, methidathion,methiocarb, methocrotophos, methomyl, methoprene, methoxychlor,methoxyfenozide, methyl bromide, methyl isothiocyanate,methylchloroform, methylene chloride, metofluthrin, metolcarb,metoxadiazone, mevinphos, mexacarbate, milbemectin, milbemycin oxime,mipafox, mirex, molosultap, monocrotophos, monomehypo, monosultap,morphothion, moxidectin, naftalofos, naled, naphthalene, nicotine,nifluridide, nitenpyram, nithiazine, nitrilacarb, novaluron,noviflumuron, omethoate, oxamyl, oxydemeton-methyl, oxydeprofos,oxydisulfoton, para-dichlorobenzene, parathion, parathion-methyl,penfluron, pentachlorophenol, permethrin, phenkapton, phenothrin,phenthoate, phorate, phosalone, phosfolan, phosmet, phosnichlor,phosphamidon, phosphine, phoxim, phoxim-methyl, pirimetaphos,pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, potassium arsenite,potassium thiocyanate, pp'-DDT, prallethrin, precocene I, precocene II,precocene III, primidophos, profenofos, profluralin, promacyl,promecarb, propaphos, propetamphos, propoxur, prothidathion, prothiofos,prothoate, protrifenbute, pyraclofos, pyrafluprole, pyrazophos,pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyridaben,pyridalyl, pyridaphenthion, pyrifluquinazon, pyrimidifen, pyrimitate,pyriprole, pyriproxyfen, quassia, quinalphos, quinalphos-methyl,quinothion, rafoxanide, resmethrin, rotenone, ryania, sabadilla,schradan, selamectin, silafluofen, silica gel, sodium arsenite, sodiumfluoride, sodium hexafluorosilicate, sodium thiocyanate, sophamide,spinetoram, spinosad, spiromesifen, spirotetramat, sulcofuron,sulcofuron-sodium, sulfluramid, sulfotep, sulfoxaflor, sulfurylfluoride, sulprofos, tau-fluvalinate, tazimcarb, TDE, tebufenozide,tebufenpyrad, tebupirimfos, teflubenzuron, tefluthrin, temephos, TEPP,terallethrin, terbufos, tetrachloroethane, tetrachlorvinphos,tetramethrin, tetramethylfluthrin, theta-cypermethrin, thiacloprid,thiamethoxam, thicrofos, thiocarboxime, thiocyclam, thiocyclam oxalate,thiodicarb, thiofanox, thiometon, thiosultap, thiosultap-disodium,thiosultap-monosodium, thuringiensin, tolfenpyrad, tralomethrin,transfluthrin, transpermethrin, triarathene, triazamate, triazophos,trichlorfon, trichlormetaphos-3, trichloronat, trifenofos, triflumuron,trimethacarb, triprene, vamidothion, vaniliprole, XMC, xylylcarb,zeta-cypermethrin, zolaprofos, and any combinations thereof.

Additionally, the compounds described herein may be combined withherbicides that are compatible with the compounds of the presentdisclosure in the medium selected for application, and not antagonisticto the activity of the present compounds to form pesticidal mixtures andsynergistic mixtures thereof. The fungicidal compounds of the presentdisclosure may be applied in conjunction with one or more herbicides tocontrol a wide variety of undesirable plants. When used in conjunctionwith herbicides, the presently claimed compounds may be formulated withthe herbicide(s), tank-mixed with the herbicide(s) or appliedsequentially with the herbicide(s). Typical herbicides include, but arenot limited to: 4-CPA; 4-CPB; 4-CPP; 2,4-D; 3,4-DA; 2,4-DB; 3,4-DB;2,4-DEB; 2,4-DEP; 3,4-DP; 2,3,6-TBA; 2,4,5-T; 2,4,5-TB; acetochlor,acifluorfen, aclonifen, acrolein, alachlor, allidochlor, alloxydim,allyl alcohol, alorac, ametridione, ametryn, amibuzin, amicarbazone,amidosulfuron, aminocyclopyrachlor, aminopyralid, amiprofos-methyl,amitrole, ammonium sulfamate, anilofos, anisuron, asulam, atraton,atrazine, azafenidin, azimsulfuron, aziprotryne, barban, BCPC,beflubutamid, benazolin, bencarbazone, benfluralin, benfuresate,bensulfuron, bensulide, bentazone, benzadox, benzfendizone, benzipram,benzobicyclon, benzofenap, benzofluor, benzoylprop, benzthiazuron,bicyclopyrone, bifenox, bilanafos, bispyribac, borax, bromacil,bromobonil, bromobutide, bromofenoxim, bromoxynil, brompyrazon,butachlor, butafenacil, butamifos, butenachlor, buthidazole, buthiuron,butralin, butroxydim, buturon, butylate, cacodylic acid, cafenstrole,calcium chlorate, calcium cyanamide, cambendichlor, carbasulam,carbetamide, carboxazole chlorprocarb, carfentrazone, CDEA, CEPC,chlomethoxyfen, chloramben, chloranocryl, chlorazifop, chlorazine,chlorbromuron, chlorbufam, chloreturon, chlorfenac, chlorfenprop,chlorflurazole, chlorflurenol, chloridazon, chlorimuron, chlornitrofen,chloropon, chlorotoluron, chloroxuron, chloroxynil, chlorpropham,chlorsulfuron, chlorthal, chlorthiamid, cinidon-ethyl, cinmethylin,cinosulfuron, cisanilide, clethodim, cliodinate, clodinafop, clofop,clomazone, clomeprop, cloprop, cloproxydim, clopyralid, cloransulam,CMA, copper sulfate, CPMF, CPPC, credazine, cresol, cumyluron,cyanatryn, cyanazine, cycloate, cyclosulfamuron, cycloxydim, cycluron,cyhalofop, cyperquat, cyprazine, cyprazole, cypromid, daimuron, dalapon,dazomet, delachlor, desmedipham, desmetryn, di-allate, dicamba,dichlobenil, dichloralurea, dichlormate, dichlorprop, dichlorprop-P,diclofop, diclosulam, diethamquat, diethatyl, difenopenten, difenoxuron,difenzoquat, diflufenican, diflufenzopyr, dimefuron, dimepiperate,dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimexano,dimidazon, dinitramine, dinofenate, dinoprop, dinosam, dinoseb,dinoterb, diphenamid, dipropetryn, diquat, disul, dithiopyr, diuron,DMPA, DNOC, DSMA, EBEP, eglinazine, endothal, epronaz, EPTC, erbon,esprocarb, ethalfluralin, ethametsulfuron, ethidimuron, ethiolate,ethofumesate, ethoxyfen, ethoxysulfuron, etinofen, etnipromid,etobenzanid, EXD, fenasulam, fenoprop, fenoxaprop, fenoxaprop-P,fenoxasulfone, fenteracol, fenthiaprop, fentrazamide, fenuron, ferroussulfate, flamprop, flamprop- M, flazasulfuron, florasulam, fluazifop,fluazifop-P, fluazolate, flucarbazone, flucetosulfuron, fluchloralin,flufenacet, flufenican, flufenpyr, flumetsulam, flumezin, flumiclorac,flumioxazin, flumipropyn, fluometuron, fluorodifen, fluoroglycofen,fluoromidine, fluoronitrofen, fluothiuron, flupoxam, flupropacil,flupropanate, flupyrsulfuron, fluridone, flurochloridone, fluroxypyr,flurtamone, fluthiacet, fomesafen, foramsulfuron, fosamine, furyloxyfen,glufosinate, glufosinate-P, glyphosate, halauxifen, halosafen,halosulfuron, haloxydine, haloxyfop, haloxyfop-P, hexachloroacetone,hexaflurate, hexazinone, imazamethabenz, imazamox, imazapic, imazapyr,imazaquin, imazethapyr, imazosulfuron, indanofan, indaziflam, iodobonil,iodomethane, iodosulfuron, ioxynil, ipazine, ipfencarbazone, iprymidam,isocarbamid, isocil, isomethiozin, isonoruron, isopolinate, isopropalin,isoproturon, isouron, isoxaben, isoxachlortole, isoxaflutole,isoxapyrifop, karbutilate, ketospiradox, lactofen, lenacil, linuron,MAA, MAMA, MCPA, MCPA-thioethyl, MCPB, mecoprop, mecoprop-P, medinoterb,mefenacet, mefluidide, mesoprazine, mesosulfuron, mesotrione, metam,metamifop, metamitron, metazachlor, metazosulfuron, metflurazon,methabenzthiazuron, methalpropalin, methazole, methiobencarb,methiozolin, methiuron, methometon, methoprotryne, methyl bromide,methyl isothiocyanate, methyldymron, metobenzuron, metobromuron,metolachlor, metosulam, metoxuron, metribuzin, metsulfuron, molinate,monalide, monisouron, monochloroacetic acid, monolinuron, monuron,morfamquat, MSMA, naproanilide, napropamide, naptalam, neburon,nicosulfuron, nipyraclofen, nitralin, nitrofen, nitrofluorfen,norflurazon, noruron, OCH, orbencarb, ortho-dichlorobenzene,orthosulfamuron, oryzalin, oxadiargyl, oxadiazon, oxapyrazon,oxasulfuron, oxaziclomefone, oxyfluorfen, parafluron, paraquat,pebulate, pelargonic acid, pendimethalin, penoxsulam, pentachlorophenol,pentanochlor, pentoxazone, perfluidone, pethoxamid, phenisopham,phenmedipham, phenmedipham-ethyl, phenobenzuron, phenylmercury acetate,picloram, picolinafen, pinoxaden, piperophos, potassium arsenite,potassium azide, potassium cyanate, pretilachlor, primisulfuron,procyazine, prodiamine, profluazol, profluralin, profoxydim,proglinazine, prometon, prometryn, propachlor, propanil, propaquizafop,propazine, propham, propisochlor, propoxycarbazone, propyrisulfuron,propyzamide, prosulfalin, prosulfocarb, prosulfuron, proxan, prynachlor,pydanon, pyraclonil, pyraflufen, pyrasulfotole, pyrazolynate,pyrazosulfuron, pyrazoxyfen, pyribenzoxim, pyributicarb, pyriclor,pyridafol, pyridate, pyriftalid, pyriminobac, pyrimisulfan, pyrithiobac,pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quinoclamine,quinonamid, quizalofop, quizalofop-P, rhodethanil, rimsulfuron,saflufenacil, S-metolachlor, sebuthylazine, secbumeton, sethoxydim,siduron, simazine, simeton, simetryn, SMA, sodium arsenite, sodiumazide, sodium chlorate, sulcotrione, sulfallate, sulfentrazone,sulfometuron, sulfosulfuron, sulfuric acid, sulglycapin, swep, TCA,tebutam, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim,terbacil, terbucarb, terbuchlor, terbumeton, terbuthylazine, terbutryn,tetrafluron, thenylchlor, thiazafluron, thiazopyr, thidiazimin,thidiazuron, thiencarbazone-methyl, thifensulfuron, thiobencarb,tiocarbazil, tioclorim, topramezone, tralkoxydim, triafamone,tri-allate, triasulfuron, triaziflam, tribenuron, tricamba, triclopyr,tridiphane, trietazine, trifloxysulfuron, trifluralin, triflusulfuron,trifop, trifopsime, trihydroxytriazine, trimeturon, tripropindan,tritac, tritosulfuron, vernolate, and xylachlor.

Another embodiment of the present disclosure is a method for the controlor prevention of fungal attack. This method comprises applying to thesoil, plant, roots, foliage, or locus of the fungus, or to a locus inwhich the infestation is to be prevented (for example applying to cerealor grape plants), a fungicidally effective amount of one or more of thecompounds of Formula I. The compounds are suitable for treatment ofvarious plants at fungicidal levels, while exhibiting low phytotoxicity.The compounds may be useful both in a protectant and/or an eradicantfashion.

The compounds have been found to have significant fungicidal effectparticularly for agricultural use. Many of the compounds areparticularly effective for use with agricultural crops and horticulturalplants.

It will be understood by those skilled in the art that the efficacy ofthe compound for the foregoing fungi establishes the general utility ofthe compounds as fungicides.

The compounds have broad ranges of activity against fungal pathogens.Exemplary pathogens may include, but are not limited to, causing agentof wheat leaf blotch (Zymoseptoria tritici), wheat brown rust (Pucciniatriticina), wheat stripe rust (Puccinia striiformis), scab of apple(Venturia inaequalis), powdery mildew of grapevine (Uncinula necator),barley scald (Rhynchosporium secalis), blast of rice (Magnaporthegrisea), rust of soybean (Phakopsora pachyrhizi), glume blotch of wheat(Leptosphaeria nodorum), powdery mildew of wheat (Blumeria graminis f.sp. tritici), powdery mildew of barley (Blumeria graminis f. sp.hordei), powdery mildew of cucurbits (Erysiphe cichoracearum),anthracnose of cucurbits (Glomerella lagenarium), leaf spot of beet(Cercospora beticola), early blight of tomato (Alternaria solani), andspot blotch of barley (Cochliobolus sativus). The exact amount of theactive material to be applied is dependent not only on the specificactive material being applied, but also on the particular actiondesired, the fungal species to be controlled, and the stage of growththereof, as well as the part of the plant or other product to becontacted with the compound. Thus, all the compounds, and formulationscontaining the same, may not be equally effective at similarconcentrations or against the same fungal species.

The compounds are effective in use with plants in a disease-inhibitingand phytologically acceptable amount. The term “disease-inhibiting andphytologically acceptable amount” refers to an amount of a compound thatkills or inhibits the plant disease for which control is desired, but isnot significantly toxic to the plant. This amount will generally be fromabout 0.1 to about 1000 ppm (parts per million), with 1 to 500 ppm beingpreferred. The exact concentration of compound required varies with thefungal disease to be controlled, the type of formulation employed, themethod of application, the particular plant species, climate conditions,and the like. A suitable application rate is typically in the range fromabout 0.10 to about 4 pounds/acre (about 0.01 to 0.45 grams per squaremeter, g/m²).

Any range or desired value given herein may be extended or alteredwithout losing the effects sought, as is apparent to the skilled personfor an understanding of the teachings herein.

The compounds of Formula I may be made using well-known chemicalprocedures. Intermediates not specifically mentioned in this disclosureare either commercially available, may be made by routes disclosed inthe chemical literature, or may be readily synthesized from commercialstarting materials utilizing standard procedures.

General Schemes

The following schemes illustrate approaches to generating picolinamidecompounds of Formula (I). The following descriptions and examples areprovided for illustrative purposes and should not be construed aslimiting in terms of substituents or substitution patterns.

Compounds of Formula 1.3 and 1.4 wherein R₄ is as originally defined,can be prepared by the methods shown in Scheme 1, steps a-c. Compoundsof Formula 1.1, wherein R₄ is as originally defined, can be prepared bytreatment of halogens (X) of Formula 1.0, wherein R₄ is as originallydefined, first under standard Grignard conditions, using magnesium metaland an alkali base, such as lithium chloride, in a polar, aproticsolvent such as tetrahydrofuran (THF) or diethyl ether (Et2O), at atemperature of about 0° C. to about 70° C., to afford the Grignardintermediate. The solution is then treated with a metal catalyst, suchas iron (III) acetylacetonate, followed by allyl chloride, in a polaraprotic solvent, such as THF, at a temperature of about 0° C. to about70° C., to give compounds of Formula 1.1, wherein R₄ is as previouslydefined, and shown in step a. Generally, the composition of compounds ofFormula 1.1 derived from this process is a mixture of allyl and E, Zisomers of the styrene derived products. Compounds of Formula 1.1,wherein R₄ is as previously defined, can be isomerized to compounds ofFormula 1.2 by treating with a metal catalyst system, such asbis(dibenzylideneactone)palladium (O), a phosphine coordinating reagent,such as tri-tert-butylphosphine, and an acid chloride, such asisobutyryl chloride, in an aromatic hydrocarbon solvent such as toluene,at a temperature of about 25° C. to 100° C., to afford compounds ofFormula 1.2, wherein R₄ is as originally defined, and shown in step b.Alternatively, compounds of Formula 1.2, wherein R₄ is as originallydefined, can be isomerized using the conditions of Mayer, M.; Welther,A.; Jacobi von Wangelin, A. Chem Cat Chem. 2011, 3, 1567-1571, and shownin step b. Epoxides of Formulas 1.3 and 1.4, wherein R₄ is as previouslydefined, can be obtained by a catalytic asymmetric epoxidation methodusing oxone as oxidant and a fructose derived ketone as described byWang, Z-X; Tu, Y.; Frohn, M.; Zhang, J-R.; Shi, Y. J. Am. Chem. Soc.1997, 119, 11224-11235, and depicted in step c. It will be understood bythose skilled in the art that epoxides of Formulae 1.3 and 1.4, whereinR₄ is as previously defined, can be prepared by other catalyticasymmetric epoxidation methods, including, but not limited to,dioxiranes derived from other chiral ketones; catalytic metal salencomplexes using an oxidant, such

as dioxygen or sodium hypochlorite; chiral iminium salts using oxone asthe oxidizing species; chiral organic oxaziridine salts; and enzymaticepoxidation biocatalysts, such as monooxygenases and hydrolases.

Compounds of Formulas 2.1 and 2.2, wherein R₃, R_(3′) and R₄ are aspreviously defined, and R₃ and R_(3′) may or may not be equivalent, canbe prepared by the method shown in Scheme 2, step a. Subjection ofepoxides of Formulas 1.3 and 1.4, wherein R₄ is as previously defined,to an

organometallic nucleophile, such as an alkyl magnesium halide, in thepresence of a metal halide, such as copper iodide, in a polar, aproticsolvent, such as THF or Et2O, at a temperature of about −78° C. to 55°C., affords compounds of Formulas 2.1 and 2.2, wherein R₃, R_(3′) and R₄are as previously defined, and R₃ and R_(3′) may or may not beequivalent, and shown in step a.

In certain cases, it is beneficial to employ an alkenyl organometallicreagent as the carbon nucleophile and shown in Scheme 3. Compounds ofFormulas 3.1 and 3.3, wherein R₃ and R₄ are as previously defined, canbe prepared by treating epoxides of Formulas 1.3 and 1.4, wherein R₄ isas previously defined, with an alkenyl magnesium halide, such asprop-1-en-2-ylmagnesium bromide, in the presence of a metal halide, suchas copper iodide, in a polar, aprotic solvent, such as THF or Et2O, at atemperature of about −78° C. to 25° C., and shown in step a. Compoundsof

Formulas 3.2 and 3.4, wherein R₃ and R₄ are as previously defined, canbe prepared by treament of compounds of Formulas 3.1 and 3.3, wherein R₃and R₄ are as previously defined, with a metal hydrogenation catalyst,such as tris(triphenylphosphine)rhodium(I) chloride (Wilkinson'scatalyst) in a polar, aprotic solvent, such as THF, in the presence of ahydrogen atmosphere (1-4 atm); or, alternatively, with palladiumabsorbed on carbon, in a polar solvent, such as THF, in the presence ofa hydrogen atmosphere (1-4 atm), and shown in step b.

In certain additional examples, compounds of Formula 4.2, wherein R₃,R_(3′) and R₄ are as previously defined and R₃ and R_(3′) may or may notbe equivalent, can be prepared by the procedure shown in Scheme 4, stepsa and b. Compounds of Formula 2.1, wherein R₃, R_(3′) and R₄ are aspreviously defined and R₃ and R_(3′) may or may not be equivalent, canbe treated with an oxidizing reagent, such as the Dess-Martinperiodinane, in a polar solvent such as dichloromethane (CH₂Cl₂), at atemperature of about 0° C. to 50° C., to give compounds of Formula 4.1,wherein R₃, R_(3′) and R₄ are as previously defined and R₃ and R_(3′)may or may not be equivalent, and shown in a. Compounds of Formula 4.1,wherein R₃, R_(3′) and R₄ are as previously defined and R₃ and R_(3′)may or may not be equivalent, can be treated with a chiraloxazaborolidine catalyst, such as(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole, inthe presence of a boron hydride reducing agent, such as borane-dimethylsulfide complex, in an aprotic solvent, such as toluene or

THF, at a temperature from about −78° C. to about room temperature, toafford compounds of Formula 4.2, wherein R₃, R_(3′) and R₄ are aspreviously defined and R₃ and R_(3′) may or may not be equivalent, andshown in b. Typical diastereomeric ratios obtained in b are generally inthe 2:1 to 5:1 range with the anti isomer being favored over the syn. Itwill be understood by those skilled in the art that compounds of Formula4.1, wherein R₃, R_(3′) and R₄ are as previously defined and R₃ andR_(3′) may or may not be equivalent, can be enantioselective reduced byother chiral catalyst/hydride reducing agent combinations, including,but not limited to, chirally modified lithium aluminum hydride or sodiumborohydride reagents, phosphoramide catalysts, transfer hydrogenationcatalyzed by chiral metal complexes, phase transfer catalysts, orenantioselective hydrogenation of pro-chiral ketones by enzymaticcatalysis.

In certain additional examples, compounds of Formula 5.5 and 5.9,wherein R₃, R_(3′) and R₄ are as previously defined and R₃ and R_(3′)may or may not be equivalent, can be prepared by the procedure shown inScheme 5, steps a-i. The compound of Formula 5.0 can be treated with anaryl or heteroaryl organometallic reagent, such as phenylmagnesiumbromide, in a polar aprotic solvent, such as THF or Et₂O, at atemperature of about 0° C. to room temperature, to afford compounds ofFormula 5.1, wherein R₄ is as originally defined, and shown in step a.Subjection of compounds of Formula 5.1 to an oxidization procedure, suchas the Swern process (oxalyl chloride, DMSO, Et₃N, CH₂Cl₂), affordscompounds of Formula 5.2, wherein R₄ is as originally defined, depictedin b. Compounds of Formula 5.3, wherein R₃, R_(3′) and R₄ are aspreviously defined, and R₃ and R_(3′) may or

may not be equivalent, can be obtained by treating compounds of Formula5.2, wherein R₄ is as originally defined, with an organometallicnucleophile, such as isopropylmagnesium bromide, in a polar aproticsolvent, such as THF or Et₂O, at a temperature of about 0° C. to roomtemperature, as depicted in step c. Compounds of Formula 5.4, whereinR₃, R_(3′), and R₄ are as previously defined and R₃ and R_(3′) may ormay not be equivalent, and R₄ is not an electron-deficient aryl orheteroaryl group, can be obtained by treating the compounds of Formula5.3, wherein R₃, R_(3′) are as previously defined and may or may not beequivalent, and R₄ is not an electron-deficient aryl or heteroarylgroup, with a mixture of a hydride reagent, such as triethylsilane(Et₃SiH), and an acid, such as 2,2,2-trifluoroacetic acid (TFA) in ahalogenated solvent such as dichloromethane (DCM) at a temperature ofabout 0° C. to 23° C., as depicted in d. Compounds of Formula 5.5,wherein R₃, R_(3′), and R₄ are as originally defined and R₃ may or maynot be equivalent to R_(3′), can be prepared from compounds of Formula5.4, wherein R₃, R_(3′), and R₄ are as originally defined and R₃ may ormay not be equivalent to R_(3′), by treating with a metal catalyst suchas palladium on carbon (Pd/C) in a polar protic solvent, such as ethanol(EtOH), in a hydrogen atmosphere (1-4 atm) at a temperature of about 25°C. to 65° C., or with an alternate source of hydrogen, such ascyclohexene, in a polar solvent such as EtOH, and shown in step e. Incertain other cases, it is beneficial to synthesize compounds of Formula5.9, wherein R₃ and R₄ are as originally defined, by the method shown insteps f-i. Compounds of Formula 5.2, wherein R₄ is as previouslydefined, can be treated with an alkenyl organometallic reagent, such asisopropenylmagnesium bromide, in a polar aprotic solvent, such as THF orEt₂O, at a temperature of about 0° C. to room temperature, to affordcompounds of Formula 5.6, wherein R₃ and R₄ are as originally defined,and shown in step f. Compounds of Formula 5.7, wherein R₃ and R₄ are aspreviously defined, can be prepared by treament of compounds of Formula5.6, wherein R₃ and R₄ are as previously defined, with a metalhydrogenation catalyst, such as tris(triphenylphosphine)rhodium(I)chloride (Wilkinson's catalyst) in a polar, aprotic solvent, such asTHF, in the presence of a hydrogen atmosphere (1-4 atm), and shown in g.Compounds of Formula 5.8, wherein R₃ and R₄ are as previously defined,and R₄ is not an electron-deficient aryl or heteroaryl group, can beobtained by treating the compounds of Formula 5.7, wherein R₃ and R₄ areas previously defined, and R₄ is not an electron-deficient aryl orheteroaryl group, with a mixture of a hydride reagent, such astriethylsilane (Et₃SiH), and an acid, such as 2,2,2-trifluoroacetic acid(TFA) in a halogenated solvent such as dichloromethane (DCM) at atemperature of about 0° C. to 23° C., as depicted in h. Compounds ofFormula 5.9, wherein R₃ and R₄ are as previously defined, can beprepared by treament of compounds of Formula 5.8, wherein R₃ and R₄ areas previously defined, with a metal hydrogenation catalyst, such astris(triphenylphosphine)rhodium(I) chloride (Wilkinson's catalyst) in apolar, aprotic solvent, such as THF, in the presence of a hydrogenatmosphere (1-4 atm); or, alternatively, with palladium absorbed oncarbon, in a polar solvent, such as THF, in the presence of a hydrogenatmosphere (1-4 atm), and shown in step i.

In certain other examples, compounds of Formula 5.5, wherein R₃, R_(3′),and R₄, are as originally defined, and R₃ and R_(3′) may or may not beequivalent, may also be prepared according to the method outlined inScheme 6, steps a and b. Treatment of compounds of Formula 2.1, whereinR₃, R_(3′), and R₄ are as originally defined, and R₃ and R_(3′) may ormay not be equivalent, with an

electron deficient benzoic acid, such as p-nitrobenzoic acid, aphosphine nucleophile, such as triphenylphosphine; and a diazenecoupling reagent, such as diethyl (E)-diazene-1,2-dicarboxylate, in apolar, aprotic solvent, such as THF, at a temperature of about 0° C. toabout 25° C. affords compounds of Formula 6.1, wherein R₃, R_(3′), andR₄ are as originally defined, and R₃ and R_(3′) may or may not beequivalent, as depicted in step a. In step b, compounds of Formula 6.1,wherein R₃, R_(3′), and R₄ are as originally defined, and R₃ and R_(3′)may or may not be equivalent, can be treated with an aqueous solution ofan inorganic base, such as sodium hydroxide, in a polar aprotic solvent,such as THF, at a temperature of about 0° C. to about 40° C. to affordcompounds of Formula 5.5, wherein R₃, R_(3′), and R₄ are as originallydefined, and R₃ and R_(3′) may or may not be equivalent.

Compounds of Formula 7.2, wherein R₁, R₃, R_(3′), R₄, and R₁₁, are asoriginally defined, and R₃ and R_(3′) may or may not be equivalent, maybe prepared according to the method outlined in Scheme 7, step a.Alcohols of Formula 5.5, wherein R₃, R_(3′), and R₄, are as originallydefined, and R₃ and R_(3′) may or may not be equivalent, can be treatedwith compounds of Formula 7.1, wherein R₁ and R₁₁ are as originallydefined, a coupling reagent, such as3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine hydrochloride(EDC) or a polymer-supported carbodiimide (PS-CDI), and a catalyst, suchas N,N-dimethylpyridin-4-amine (DMAP), in a halogenated or polar,aprotic solvent, such as CH₂Cl₂ or THF to afford compounds of Formula7.2, wherein R₁, R₃, R_(3′), R₄, and R₁₁, are as originally defined, andR₃ and R_(3′) may or may not be equivalent, as shown in step a.

Compounds of Formula 7.2, wherein R₁, R₃, R_(3′), R₄, and R₁₁, are asoriginally defined, and R₃ and R_(3′) may or may not be equivalent, mayalso be prepared according to the method outlined in Scheme 8, step a.Alcohols of Formula 2.1, wherein R₃, R_(3′), and R₄, are as originally

defined, and R₃ and R_(3′) may or may not be equivalent, can be treatedwith with compounds of Formula 7.1, wherein Ru and Ru are as originallydefined, a phosphine reagent, such as triphenylphosphine, and a diazinedicarboxylate electrophile, such as diisopropyl(E)-diazene-1,2-dicarboxylate (DIAD), in a polar aprotic solvent, suchas THF, at a temperature of about 0° C. to 25° C. to afford compounds ofFormula 7.2, wherein R₁, R₃, R_(3′), R₄, and R₁₁, are as originallydefined, and R₃ and R_(3′) may or may not be equivalent, as shown instep a.

Compounds of Formula 9.5, wherein R₁, R₂, R₃, R_(3′), R₄, R₆, and R₁₁,are as originally defined, and R₃ and R_(3′) may or may not beequivalent, can be prepared according to the methods outlined in Scheme9, steps a-d. Compounds of Formula 9.1, wherein R₁, R₂, R₃, R_(3′), R₄,and R₁₁, are as originally defined, and R₃ and R_(3′) may or may not beequivalent, but not alkenyl, can be treated with an acid, such as a 4 Nsolution of HCl in dioxane, in a halogenated solvent such as CH₂Cl₂ toafford compounds of Formula 9.2, wherein R₁, R₂, R₃, R_(3′), R₄, andR₁₁, are as originally defined, and R₃ and R_(3′) may or may not beequivalent, but not alkenyl, as shown in step a. Compounds of Formula9.3, wherein R₁, R₂, R₃, R_(3′), R₄, and R₁₁, are as originally defined,and R₃ and R_(3′) may or may not be equivalent, can be prepared bytreating compounds of Formula 9.1, wherein R₁, R₂, R₃, R_(3′), R₄, andR₁₁, are as originally defined, and R₃ and R_(3′) may or may not beequivalent, with an acid, such as 2,2,2-trifluoroacetic acid, in ahalogenated solvent such as CH₂Cl₂, as shown in step c. Compounds ofFormulas 9.2 and 9.3, wherein R₁, R₂, R₃, R_(3′), R₄, and R₁₁, are asoriginally defined, and R₃ and R_(3′) may or may not be equivalent, canbe treated with compounds of Formula 9.4, wherein R₆ is as originallydefined, in the presence of a base, such as diisopropylethylamine, and apeptide coupling reagent, such asbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) or O-(7-azabenzo-triazol-1-yl)-N,N,N′, N′-tetramethyluroniumhexafluorophosphate (HATU), in an halogenated solvent such as CH₂Cl₂, toafford compounds of Formula 9.5, wherein R₁, R₂, R₃, R_(3′), R₄, R₆ andR₁₁, are as originally defined, and R₃ and R_(3′) may or may not beequivalent, as shown in steps b and d.

Compounds of Formula 10.1, wherein R₁, R₂, R₃, R_(3′), R₄, R₆, R₇, andR₁₁, are as originally defined, and R₃ and R_(3′) may or may not beequivalent, can be prepared according to the method outlined in Scheme10, steps a or b. Compounds of Formula 9.5, wherein R₁, R₂, R₃, R_(3′),R₄, R₆ and R₁₁, are as originally defined, and R₃ and R_(3′) may or maynot be equivalent, can be treated with an appropriate alkyl halide withor without a reagent such as sodium iodide (NaI) and an alkali carbonatebase, such as sodium (Na₂CO₃) or potassium carbonate (K₂CO₃), in asolvent such as acetone, as shown in step a. Or, alternatively, bytreatment with an acyl halide or anhydride in the presence of an aminebase, such as pyridine, NEt₃, DMAP, or mixtures thereof, in an aproticsolvent, such as CH₂Cl₂, to afford compounds of Formula 10.1, whereinR₁, R₂, R₃, R_(3′), R₄, R₆, R₇, and R₁₁, are as originally defined, andR₃ and R_(3′) may or may not be equivalent, as shown in step b.

Compounds of Formula 11.1 and 11.2, wherein R₁, R₂, R₃, R_(3′), R₄, R₆,R₇, and R₁₁, are as originally defined, and R₃ and R_(3′) may or may notbe equivalent, can be prepared according to the method outlined inScheme 11, steps a and b. Compounds of Formula 9.5, wherein R₁, R₂, R₃,R_(3′), R₄, R₆, and R₁₁, are as originally defined, and R₃ and R_(3′)may or may not be equivalent, can be treated with a thionating reagentsuch as phosphorus pentasulfide, an additive, such ashexamethyldisiloxane, optionally in a polar aprotic solvent such asacetonitrile (CH₃CN), at a temperature of about 0° C. to 80° C. toafford compounds of Formula 11.1, wherein R₁, R₂, R₃, R_(3′), R₄, R₆,and R₁₁, are as originally defined, and R₃ and R_(3′) may or may not beequivalent, and shown in step a. It will be understood by those skilledin the art that compounds such as Formula 11.1 may also be preparedusing other thionating agents including, but not limited to: sulfur,sulfhydric acid, sodium sulfide, sodium hydrosulfide, boron trisulfide,bis(diethylaluminum)sulfide, ammonium sulfide, Lawesson's reagent,ammonium O,O′-diethyl dithiophosphate, rhodanine, or a polymer supportedthionating reagent. Additives can include, but not limited to, aluminumoxide (Al₂O₃); inorganic bases, such as potassium carbonate and sodiumbicarbonate; organic bases, such as triethylamine, diethylaniline,pyridine and morpholine. Optional solvents can include, but not limitedto, aliphatic, alicyclic or aromatic hydrocarbons, such as hexane,cyclohexane or toluene; halogenated hydrocarbons, such asdichloromethane, 1,2-dichloroethane and chlorobenzene; ethers, such asdiethyl ether, 1,4-dioxane, THF and 1,2-dimethoxyethane; and other polaraprotic solvents such as pyridine and hexamethylphosphoramide (HMPA). Instep b, treatment of compounds of Formula 11.1, wherein R₁, R₂, R₃,R_(3′), R₄, R₆, and R₁₁, are as originally defined, and R₃ and R_(3′)may or may not be equivalent, with an appropriate alkyl halide with orwithout a reagent such as sodium iodide (Nal) and an alkali carbonatebase, such as sodium carbonate (Na₂CO₃) or potassium carbonate (K₂CO₃),in a solvent like acetone at a temperature of about 55° C., or bytreatment with an acyl halide or anhydride in the presence of an aminebase, such as pyridine, triethylamine (Et₃N), DMAP, or mixtures thereof,in an optional aprotic solvent such as DCM, at a temperature of about23° C., can afford compounds of Formula 11.2 wherein R₁, R₂, R₃, R_(3′),R₄, R₆, R₇, and R₁₁, are as originally defined, and R₃ and R_(3′) may ormay not be equivalent.

Compounds of Formula 12.1, wherein R₁, R₂, R₃, R_(3′), R₄, R₆, and R₁₁,are as originally defined, and R₃ and R_(3′) may or may not beequivalent, can be prepared according to the method outlined in Scheme12, step a. Compounds of Formula 9.5, wherein R₁, R₂, R₃, R_(3′), R₄,R₆, and R₁₁, are as originally defined, and R₃ and R_(3′) may or may notbe equivalent, can be treated with a oxidizing reagent such asm-chloroperbenzoic acid (mCPBA) in a polar solvent such asdichloromethane (CH₂Cl₂), at a temperature of about 0° C. to 50° C., togive compounds of Formula 12.1, as shown in a. It will be understood bythose skilled in the art that compounds of Formula 12.1, wherein R₁, R₂,R₃, R_(3′), R₄, R₆, and R₁₁, are as originally defined, and R₃ andR_(3′) may or may not be equivalent, may also be prepared using otheroxidizing agents, including, bit not limited to:

hydrogen peroxide, hydrogen peroxide-urea complex, magnesiummonoperoxyphthalate hexahydrate (MMPP), peroxyacetic acid, oxone, sodiumperchlorate or dimethyl dioxirane.

Compounds of Formula 13.1 wherein R₁, R₂, R₃, R_(3′), R₄, R₆, and R₁₁,are as originally defined, and R₃ and R_(3′) may or may not beequivalent, can be prepared according to the method outlined in Scheme13, step a. Compounds of Formula 9.5, wherein R₁, R₂, R₃, R_(3′), R₄,R₆, and R₁₁, are as originally defined, and R₃ and R_(3′) may or may notbe equivalent, can be treated with a diactivated carbonyl reagent suchas triphosgene, with a base, such as pyridine, in a polar solvent, suchas dichloromethane (CH₂Cl₂), at a temperature of about 0° C. to 50° C.to afford compounds of Formula 13.1, wherein R₁, R₂, R₃, R_(3′), R₄, R₆,and R₁₁, are as originally defined, and R₃ and R_(3′) may or may not beequivalent, as depicted in a.

EXAMPLES Example 1A: Preparation of(E)-1-methyl-4-(prop-1-en-1-yl)benzene

This compound was prepared by the method of Mayer, M.; Welther, A.;Jacobi von Wangelin, A. Chem Cat Chem. 2011, 3, 1567-1571.

Example 1B: Preparation of (E)-1-fluoro-4-(prop-1-en-1-yl)benzene

To a solution of 1-allyl-4-fluorobenzene (1.35 mL, 10 mmol) in toluene(20 mL) was added bis(dibenzylideneacetone)palladium (0.115 g, 0.200mmol), tri-tert-butylphosphine (10% in hexane) (0.618 ml, 0.200 mmol)and isobutyryl chloride (0.021 ml, 0.200 mmol) in toluene (20.00 ml).The reaction was stirred at 80° C. overnight. The reaction mixture waspurified by Isco chromatography (0 to 5% Et₂O in pet ether) to providethe desired product as solution in toluene (20 mL) (1.36 g, 95%). ¹H NMR(300 MHz, CDCl₃) δ 7.32-7.10 (m, 6H), 2.35 (s, 3H). ¹⁹F NMR (376 MHz,CDCl₃) δ-115.97.

Example 1C: Preparation of(E)-4-fluoro-2-methoxy-1-(prop-1-en-1-yl)benzene

Step 1: Preparation of(E,Z)-4-fluoro-2-methoxy-1-(prop-1-en-1-yl)benzene

To a mixture of magnesium (0.79 g, 32.5 mmol) and lithium chloride (1.52g, 35.80 mmol) in THF (33 ml) at room temperature was added1-bromo-4-fluoro-2-methoxybenzene (3.13 mL, 24.39 mmol) and the reactionwas stirred at 70° C. for 1.5 hr. The reaction was then cooled to 0° C.,and Fe(acac)3 (0.574 g, 1.63 mmol) was added. After 1 minute, allylchloride (1.33 mL, 16.26 mmol) was added and the reaction was stirred at0° C. for 30 min. The mixture was warmed to room temperature over 1 hrand was heated at 70° C. overnight. The reaction was cooled and dilutedwith petroleum ether (100 mL). The reaction was then quenched by theaddition of a saturated NH₄Cl solution (100 mL). The mixture wasfiltered through a Celite® pad and the layers were separated. Theaqueous layer was extracted with petroleum ether (2×100 mL) and thecombined organic phases were dried over Na₂SO₄ and carefullyconcentrated (25° C., 250 mbar). The residue was purified by Iscochromatography (100% pet ether as the eleuent) to provide(E,Z)-4-fluoro-2-methoxy-1-(prop-1-en-1-yl)benzene (2.25 g, 83% yield)as a colorless oil. This mixture was approximately a 3:1 mixture of Eand Z isomers with a trace of the allyl isomer present. This materialwas used directly in the next step. ¹H NMR (400 MHz, CDCl₃) δ 7.31 (dd,J=8.3, 6.8 Hz, 1H), 6.65-6.53 (m, 3H), 6.14 (dq, J=15.8, 6.6 Hz, 1H),3.82 (s, 3H), 1.88 (dd, J=6.6, 1.7 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃)δ-113.30.

Step 2: Preparation of (E)-4-fluoro-2-methoxy-1-(prop-1-en-1-yl)benzene.

To a solution of (E,Z)-4-fluoro-2-methoxy-1-(prop-1-en-1-yl)benzene(2.25 g, 13.54 mmol) in toluene (27 mL) was addedbis(dibenzylideneacetone)palladium (0.156 g, 0.271 mmol),tri-tert-butylphosphine (10% in hexane) (0.84 mL, 0.271 mmol) andisobutyryl chloride (0.028 mL, 0.271 mmol). The reaction was stirred at80° C. overnight. The reaction mixture was purified by Iscochromatography (100% petroleum ether) to provide the title compound as a20:1 mixture of E vs Z isomers (2.25 g, 100%). ¹H NMR (400 MHz, CDCl₃) δ7.31 (dd, J=8.3, 6.8 Hz, 1H), 6.65-6.53 (m, 3H), 6.14 (dq, J=15.8, 6.6Hz, 1H), 3.82 (s, 3H), 1.88 (dd, J=6.6, 1.7 Hz, 3H). ¹⁹F NMR (376 MHz,CDCl₃) δ-113.30.

Example 1D: Preparation of (E)-2,4-dimethyl-1-(prop-1-en-1-yl)benzene

Step 1: Preparation of 1-allyl-2,4-dimethylbenzene.

To a solution of magnesium (1.17 g, 48.0 mmol) and lithium chloride(2.20 g, 60.0 mmol) in THF (40 ml) at room temperature was added1-bromo-2,4-dimethylbenzene (5.4 mL, 40.0 mmol) and the reaction washeated gently to reflux with a heat gun. The reaction was cooled to roomtemperature over 1 hr. The reaction was then cooled to 0° C., andFe(acac)₃ (0.71 g, 2.00 mmol) dissolved in 5 mL of THF was added. After5 minutes, allyl chloride (4.23 mL, 52.0 mmol) was added and thereaction was stirred at 0° C. for 30 min. The mixture was warmed to roomtemperature over 1 hr and was heated at 70° C. overnight. The reactionwas cooled to 0° C. and quenched by the addition of a saturated NaHCO₃solution (50 mL). The mixture was extracted with hexane (3×40 mL), thecombined organic phases were washed with brine (50 mL), dried overNa₂SO₄ and carefully concentrated (25° C., 250 mbar). The residue waspurified by Isco chromatography (100% hexane as the eluent) to provide1-allyl-2,4-dimethylbenzene (2.75 g, 15.04 mmol, 38% yield) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.11-6.87 (m, 3H), 5.93 (ddt,J=16.6, 10.1, 6.4 Hz, 1H), 5.19-4.85 (m, 2H), 3.33 (dd, J=6.4, 1.5 Hz,2H), 2.29 (s, 3H), 2.25 (s, 3H).

Step 2: Preparation of (E)-2,4-dimethyl-1-(prop-1-en-1-yl)benzene.

To a 250 mL round bottom flask charged with 1-allyl-2,4-dimethylbenzene(2.75 g, 18.81 mmol) and tris(((Z)-4-oxopent-2-en-2-yl)oxy)iron (0.332g, 0.940 mmol) in THF (38 mL) was added phenylmagnesium bromide (1.0 Min THF) (9.40 mL, 9.40 mmol) at room temperature. After stirringovernight, the reaction mixture was cooled to 0° C. and quenched by theaddition of a saturated solution of NaHCO₃ (50 mL). The combined organiclayers were extracted with hexane (3×40 mL), washed with brine (50 mL)and dried over Na₂SO₄. Upon concentration in vacuo, the crude residuewas purified via automated silica gel chromatography (100% hexanes asthe eluent) to afford (E)-2,4-dimethyl-1-(prop-1-en-1-yl)benzene (2.71g, 16.68 mmol, 89% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ7.30 (d, J=7.8 Hz, 1H), 7.05 6.86 (m, 2H), 6.56 (dd, J=15.6, 1.9 Hz,1H), 6.06 (dq, J=15.6, 6.6 Hz, 1H), 2.30 (s, 3H), 2.29 (s, 3H), 1.89(dd, J=6.6, 1.7 Hz, 3H).

Example 1E: Preparation of (E)-1-methyl-2-(prop-1-en-1-yl)benzene

This compound was prepared by the method of Franzén (Eur. J. Org. Chem.2015, 1834). To a solution of 2-methylbenzaldehyde (48.4 mL, 416 mmol)dissolved in CH₂Cl₂ (300 mL) was added 2-methylbut-2-ene (8.82 mL, 83mmol) and triphenylmethylium tetrafluoroborate (5.50 g, 16.65 mmol). Thereaction was stirred at room temperature for 20 hr. The reaction wasquenched by the additon of saturated NaHCO₃ and diluted with excessCH₂Cl₂. The organic layer was separated, dried over MgSO₄, filtered andconcentrated at low temperature and mild pressure. The resulting residuewas purified by flash chromatography (ISCO, 330 g SiO₂ column, 100% petether as the eluent) to give (E)-1-methyl-2-(prop-1-en-1-yl)benzene (10g, 71.9 mmol, 86% yield) as a clear liquid. ¹H NMR (400 MHz, CDCl₃) δ7.39 (d, J=7.0 Hz, 1H), 7.12 (qd, J=5.9, 2.1 Hz, 3H), 6.59 (dd, J=15.6,1.9 Hz, 1H), 6.10 (dq, J=15.7, 6.6 Hz, 1H), 2.32 (s, 3H), 1.90 (dd,J=6.6, 1.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 137.08, 134.77, 130.11,128.92, 126.93, 126.70, 125.99, 125.44. EIMS m/z 132.

Example 2A: 2A Denotes that this Epoxide is Commercially AvailableExample 2B: Preparation of (2S,3S)-2-methyl-3-(p-tolyl)oxirane

To a 500 mL round-bottom flask containing 75 mL of a buffer solutioncontaining 0.05 M Na₂B₄O₇-10H₂O in 4×10⁻⁴ M aqueous Na₂ (EDTA), wasadded acetonitrile (117 ml), (E)-1-methyl-4-(prop-1-en-1-yl)benzene(1.24 g, 7.69 mmol), tetrabutylammonium hydrogen sulfate (0.104 g, 0.308mmol), and(3aS,4′R,7aS)-2,2,2′,2′-tetramethyldihydrospiro[[1,3]dioxolo-[4,5-c]pyran-6,4′-[1,3]dioxolan]-7(7aH)-one(0.596 g, 2.307 mmol). The reaction mixture was cooled to 0° C. with anice bath. A solution of oxone (6.53 g, 10.61 mmol) in aqueous Na₂(EDTA)(4×10⁻⁴ M, 50 mL) and a solution of potassium carbonate (6.17 g, 44.6mmol) in water (50 mL) were added dropwise through two syringe pumpsover a period of 1.5 h (under these conditions, the reaction pH isaround 10.5; it is recommended that both oxone and K₂CO₃ be addeduniformly over 1.5 h). At this point, the reaction was immediatelyquenched by the addition of 100 mL each of petroleum ether and water.The layers were separated and the aqueous layer was extracted withpetroleum ether (3×150 mL). The combined organic layers were washed withbrine (150 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by flash chromatography (0 to 10%acetone in hexanes as the eluent) to provide(2S,3S)-2-methyl-3-(p-tolyl)oxirane (1.09 g, 6.99 mmol, 91%) as acolorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.15 (s, 4H), 3.54 (d, J=2.1Hz, 1H), 3.03 (qd, J=5.1, 2.1 Hz, 1H), 2.34 (s, 3H), 1.44 (d, J=5.1 Hz,3H). EIMS m/z 148.

Example 3A: Preparation of(1S,2R)-1-cyclobutyl-1-(4-fluoro-2-methylphenyl)propan-2-ol

A suspension of magnesium (110 mg, 4.51 mmol) was prepared in THF (3 mL)and cooled to 0° C. After 5 min, bromocyclobutane (397 μL, 4.21 mmol)was added in one portion, and the resulting solution was vigorouslystirred for 2 hr, slowly warming to room temperature. After 2 hr, thereaction was heated to 55° C. and stirred overnight. In a separate vial,a suspension of copper(I) iodide (401 mg, 2.106 mmol) in diethyl ether(7.5 mL) was cooled to −30° C. in a dry ice/acetonitrile bath. After ˜5min, the grignard solution was added via syringe over 30 seconds, andthe resulting solution was stirred at −30° C. for 30 min, yielding aturbid dark grey/brown mixture. After 30 min, the reaction was cooled to−78° C. in a dry ice/acetone bath, and(2R,3R)-2-(4-fluoro-2-methylphenyl)-3-methyloxirane (250 mg, 1.504 mmol)was added dropwise via syringe as a solution in diethyl ether (1.5 mLwith 2×0.5 mL washes). The reaction was then stirred overnight, slowlywarming to room temperature. TLC indicated consumption of startingmaterial. The reaction was quenched with sat. aq. NH₄Cl (20 mL) andextracted with diethyl ether (3×20 mL). The combined organic layers weredried over Na₂SO₄, filtered and concentrated to afford an oil. The oilwas purified via silica gel Isco column chromatography (40 g silica gelcolumn, 35 mL/min, 100% hexanes to 20% acetone : hexanes) to afford(1S,2R)-1-cyclobutyl-1-(4-fluoro-2-methylphenyl)propan-2-ol (133.4 mg,0.600 mmol, 40% yield) as a clear, colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 7.14 (dd, J=8.2, 6.1 Hz, 1H), 6.86 (t, J=8.5 Hz, 2H), 3.89 (p,J=6.4 Hz, 1H), 2.84 (dd, J=10.4, 6.0 Hz, 1H), 2.77 2.64 (m, 1H), 2.35(s, 3H), 2.24 2.12 (m, 1H), 1.86 1.58 (m, 4H), 1.44 1.24 (m, 2H), 1.13(d, J=6.3 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ-117.58, −117.59. ₁₃C NMR(101 MHz, CDCl₃) δ 160.94 (d, J=244.2 Hz), 139.81 (d, J=7.3 Hz), 134.60(d, J=3.3 Hz), 128.53 (d, J=8.0 Hz), 116.78 (d, J=20.7 Hz), 112.84 (d,J=20.6 Hz), 70.25, 53.68, 38.03, 29.54, 27.08, 21.55, 20.55 (d, J=1.7Hz), 18.16. IR (thin film) 3413, 2967, 1495, 1252, 1021, 955, 860 cm⁻¹.

Example 3B: Preparation of(2R,3S)-4-ethyl-3-(4-fluoro-2-methylphenyl)hexan-2-ol

A suspension of copper(I) iodide (401 mg, 2.106 mmol) in anhydrousdiethyl ether (7.5 mL) was cooled to −30° C. in a dry ice/acetonitrilebath. After ˜5 min, pentan-3-ylmagnesium bromide (2M in Et₂O) (2106 μL,4.21 mmol) was added via syringe over 30 seconds, and the resultingsolution was stirred at −30° C. for 30 min, yielding a turbid darkgrey/brown mixture. After 30 min, the reaction was cooled to −78° C. ina dry ice/acetone bath, and(2R,3R)-2-(4-fluoro-2-methylphenyl)-3-methyloxirane (250 mg, 1.504 mmol)was added dropwise via syringe as a solution in diethyl ether (1.5 mLwith 2×0.5 mL washes). The reaction was then stirred overnight, slowlywarming to room temperature. TLC indicated consumption of startingmaterial. The reaction was quenched with sat. aq. NH₄Cl (20 mL) andextracted with diethyl ether (3×20 mL). The combined organic layers weredried over Na₂SO₄, filtered and concentrated to afford an oil. The oilwas purified via silica gel Isco column chromatography (40 g silica gelcolumn, 35 mL/min, 100% hexanes to 20% acetone : hexanes) to afford(2R,3S)-4-ethyl-3-(4-fluoro-2-methylphenyl)hexan-2-ol (116.7 mg, 0.490mmol, 32.5% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.34 (dd,J=9.6, 6.1 Hz, 1H), 6.92-6.81 (m, 2H), 4.27 (dq, J=8.8, 4.7 Hz, 1H),2.74 (dd, J=10.2, 3.6 Hz, 1H), 2.28 (s, 3H), 1.87 (qt, J=8.2, 3.6 Hz,1H), 1.64 (dtd, J=14.9, 7.3, 4.4 Hz, 1H), 1.53 (tt, J=14.0, 6.7 Hz, 1H),1.30 1.09 (m, 2H), 1.08 0.98 (m, 1H), 0.96 (d, J=6.4 Hz, 3H), 0.92 (t,J=7.5 Hz, 3H), 0.71 (t, J=7.4 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃)d-118.01. ¹³C NMR (101 MHz, CDCl₃) δ 160.91 (d, J=243.7 Hz), 139.73 (d,J=7.1 Hz), 135.03 (d, J=3.3 Hz), 129.46 (d, J=7.9 Hz), 116.60 (d, J=20.5Hz), 112.57 (d, J=20.4 Hz), 67.19, 47.45, 41.41, 22.08, 21.91, 21.53,20.67 (d, J=1.6 Hz), 10.82, 9.78. IR (thin film) 3430, 2962, 1496, 1455,1380, 1256, 956, 860, 801 cm⁻¹.

Example 4A: Preparation of(2R,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpent-4-en-2-ol

A suspension of copper(I) iodide (0.160 g, 0.842 mmol) in anhydrousdiethyl ether (4.0 mL) was cooled to −20° C. After ˜5 min,prop-1-en-2-ylmagnesium bromide (1M in 2-Me-THF) (1.685 mL, 1.685 mmol)was added via syringe over 30 seconds, and the resulting solution wasstirred at −20° C. for 30 min. After 30 min, the reaction was cooled to−78° C. and (2R,3R)-2-(4-fluoro-2-methylphenyl)-3-methyloxirane (0.100g, 0.602 mmol) was added dropwise via syringe as a solution in diethylether (1.0 mL with 2×0.5 mL washes). The reaction was then stirredovernight, slowly warming to room temperature. TLC indicated consumptionof starting material. The reaction was quenched with sat. aq. NH₄Cl (20mL) and extracted with diethyl ether (3×20 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated to afford anoil. The oil was purified via silica gel Isco column chromatography (40g silica gel column, 35 mL/min, 100% hexanes to 20% acetone : hexanes)to afford (2R,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpent-4-en-2-ol(120.2 mg, 0.577 mmol, 96% yield) as a pale yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 7.37-7.30 (m, 1H), 6.93-6.86 (m, 2H), 4.89 (s, 2H), 4.32 (dq,J=8.8, 6.1 Hz, 1H), 3.42 (d, J=8.7 Hz, 1H), 2.34 (s, 3H), 1.59 (s, 3H),1.52 (s, 1H), 1.30 (d, J=6.1 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ-116.95.¹³C NMR (101 MHz, CDCl₃) δ 161.27 (d, J=244.8 Hz), 144.85, 140.40 (d,J=7.5 Hz), 133.79 (d, J=3.2 Hz), 128.19 (d, J=8.2 Hz), 117.47 (d, J=20.6Hz), 113.12, 112.76 (d, J=20.8 Hz), 68.13, 56.04, 21.28, 21.22, 20.03(d, J=1.5 Hz). IR (thin film) 3373, 2970, 1495, 1240, 958, 861 cm⁻¹.

Example 4B: Preparation of(2R,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-ol

To a 20 mL vial containing(2R,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpent-4-en-2-ol (120.2 mg,0.577 mmol) and palladium on carbon (5%) (184 mg, 0.087 mmol) was addedethyl acetate (2886 μL). The black reaction mixture was flushed with H₂gas via balloon. The resulting reaction was stirred at room temperaturefor 2 h, at which point TLC/UPLC indicated consumption of startingmaterial. The reaction was filtered through a plug of celute, elutingwith ethyl acetate (2×10 mL). The resulting solution was concentrated toafford an oil that was loaded directly onto a 25 g prepacked silicacolumn in a minimal amount of dichloromethane and purified using Iscosilica gel column chromatography (40 column, 40 mL/min, 100% hexanes to30% ethyl acetate:hexanes) to afford(2R,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-ol (44.9 mg, 0.214mmol, 37.0% yield) as a clear, colorless oil. ¹H NMR (400 MHz, CDCl₃) δ7.32 (dd, J=9.5, 6.1 Hz, 1H), 6.93 -6.84 (m, 2H), 4.28 (qd, J=6.3, 4.4Hz, 1H), 2.50 (dd, J=9.2, 4.4 Hz, 1H), 2.28 (s, 3H), 2.15 (dp, J=9.1,6.6 Hz, 1H), 1.42-1.13 (m, 1H), 1.06 (d, J=6.6 Hz, 3H), 1.01 (d, J=6.3Hz, 3H), 0.70 (d, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 160.93 (d,J=243.8 Hz), 139.78 (d, J=7.2 Hz), 134.96 (d, J=3.3 Hz), 129.17 (d,J=8.0 Hz), 116.64 (d, J=20.4 Hz), 112.57 (d, J=20.4 Hz), 67.70, 52.62,30.26, 21.76, 21.32, 20.77. ¹⁹F NMR (376 MHz, CDCl₃) δ-117.97.

Example 4C: Preparation of(2R,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-ol

To a 250 mL round bottom flask containing(2R,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpent-4-en-2-ol (1.16 g, 5.57mmol) and Wilkinson's catalyst (1.288 g, 1.392 mmol) was added THF (55.7ml). The reddish-brown reaction mixture was flushed with H₂ gas viaballoon. The resulting reaction was stirred at room temperatureovernight. The reaction was concentrated to a dark orange-brown oil, andthe resulting oil was loaded directly onto a 25 g prepacked silicacolumn in a minimal amount of dichloromethane and purified using Iscosilica gel column chromatography (120 column, 85 mL/min, 100% hexanes to30% ethyl acetate:hexanes) to afford(2R,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-ol (880 mg, 4.18mmol, 75% yield) as a clear, colorless oil. ¹H NMR (400 MHz, CDCl₃) δ7.32 (dd, J=9.5, 6.0 Hz, 1H), 6.92-6.84 (m, 2H), 4.28 (qd, J=6.3, 4.4Hz, 1H), 2.50 (dd, J=9.2, 4.4 Hz, 1H), 2.28 (s, 3H), 2.15 (ddd, J=13.2,6.8, 2.3 Hz, 1H), 1.31-1.17 (m, 1H), 1.06 (d, J=6.6 Hz, 3H), 1.01 (d,J=6.3 Hz, 3H), 0.70 (d, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 160.92(d, J=243.8 Hz), 139.78 (d, J=7.2 Hz), 134.95 (d, J=3.2 Hz), 129.16 (d,J=7.8 Hz), 116.64 (d, J=20.4 Hz), 112.57 (d, J=20.3 Hz), 67.70, 52.62,30.26, 21.76, 21.31, 20.76. ¹⁹F NMR (376 MHz, CDCl₃) δ-117.97.

Example 5: Preparation of (3S)-4-ethyl-3-phenylhexan-2-ol

Step 1: Preparation of (2R,3S)-4-ethyl-3-phenylhexan-2-ol.

To a suspension of copper (I) iodide (667 mg, 3.50 mmol) in Et₂O (12.5mL) cooled to −78° C. was added pentan-3-ylmagnesium bromide (2M in THF)(3.5 mL, 7.00 mmol). The reaction was warmed to −20° C. and stirred atthat temperture for 30 min. The reaction was then cooled to −78° C.followed by the addition of (2R,3R)-2-methyl-3-phenyloxirane (335 mg,2.5 mmol). The reaction was slowly warmed to room temperature andstirred overnight. The reaction was quenched by the addition of aqueoussaturated NH₄Cl. The mixture was filtered through a pad of Celite, andthe solution was extracted with Et₂O. The combined organic phases weredried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography using a 0-10%acetone/hexane mixture as the eluent to provide the title compound ascolorless oil (200 mg, 27%). ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.18 (m,5H), 4.38-4.19 (m, 1H), 2.47 (dd, J=8.5, 5.1 Hz, 1H), 1.81 (ttd, J=8.8,5.9, 3.2 Hz, 1H), 1.55-1.25 (m, 3H), 1.20 (d, J=5.6 Hz, 1H), 1.05 (d,J=6.3 Hz, 3H), 1.03-0.94 (m, 1H), 0.93 (t, J=7.4 Hz, 3H), 0.76 (t, J=7.4Hz, 3H). ESIMS (m/z) 413 [2M+H]⁺.

Step 2: Preparation of (S)-4-ethyl-3-phenylhexan-2-one.

To a solution containing (2R,3S)-4-ethyl-3-phenylhexan-2-ol (190 mg,0.921 mmol) dissolved in CH₂Cl₂ (4.6 mL) at 0° C. was added sodiumbicarbonate (774 mg, 9.21 mmol) followed by Dess-Martin periodinane (781mg, 1.842 mmol). The reaction was slowly warmed to room temperature over3 hr. The reaction was quenched by the addition of aqueous saturatedNaHCO₃ solution followed by extraction with CH₂Cl₂. The combined organicphases were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography using a0-5% acetone/hexane mixture as the eluent to provide the title compoundas colorless oil (124 mg, 63%). ¹H NMR (400 MHz, CDCl₃) δ 7.54-7.10 (m,5H), 3.61 (d, J=10.8 Hz, 1H), 2.21 (dtt, J=11.1, 7.5, 3.9 Hz, 1H), 2.09(s, 3H), 1.49 -1.32 (m, 2H), 1.31-1.15 (m, 1H), 1.05-0.94 (m, 1H), 0.89(t, J=7.4 Hz, 3H), 0.69 (t, J=7.4 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ208.87, 137.71, 128.98, 128.66, 127.12, 63.12, 41.13, 30.15, 22.76,21.03, 10.46, 9.47.

Step 3: Preparation of (3S)-4-ethyl-3-phenylhexan-2-ol.

To a stirred solution containing (S)-4-ethyl-3-phenylhexan-2-one (120mg, 0.587 mmol) and(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (1 Min toluene) (58.7 μL, 0.059 mmol) dissolved in toluene (5.9 mL) at −78°C. was added BH₃-SMe₂ complex (61.3 μL, 0.646 mmol) dropwise. Thereaction was slowly warmed to room temperature and stirred overnight.The reaction was then quenched carefully with methanol (475 μL, 11.75mmol). The mixture was diluted with H₂O and extracted with Et₂O. Thecombined organic phases were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography using a 0-10% acetone/hexane mixture as the eluent toprovide the title compound as colorless oil (110 mg, 86%). ¹H NMR showsa 3.3:1 mixture of diastereomers with the desired product being themajor diastereomer. ¹H NMR (major diastereomer) (300 MHz, CDCl₃) δ7.37-7.04 (m, 5H), 4.22 (dt, J=13.8, 6.3 Hz, 1H), 2.75 (t, J=7.5 Hz,1H), 1.85-1.73 (m, 1H), 1.55-1.21 (m, 3H), 1.18 (d, J=7.8 Hz, 1H), 1.05(d, J=6.3 Hz, 3H), 1.03-0.97 (m, 1H), 0.94 (t, J=7.4 Hz, 3H), 0.81 (t,J=7.4 Hz, 3H). ESIMS (m/z) 413 [2M+H]⁺.

Example 6: Preparation of (2S,3S)-3-(4-fluorophenyl)-4-methylpentan-2-ol

Step 1: Preparation of (2S)-2-(benzyloxy)-1-(4-fluorophenyl)propan-1-ol.

A round bottom flask was charged with (S)-2-(benzyloxy)propanal (1.0 g,6.09 mmol) dissolved in anhydrous THF (6.77 mL). This solution wascooled in an ice bath under an atmosphere of N₂ and was treated dropwisewith (4-fluorophenyl)magnesium bromide (6.70 mL, 6.70 mmol). Thereaction was monitored by TLC (20% EtOAc in hexanes) until the reactionwas complete. The reaction mixture was poured into saturated NH₄Cl andthe phases separated. The aqueous phase was extracted with EtOAc. Theorganic fractions were dried with magnesium sulfate and concentratedunder reduced pressure. The crude residue was purified by automatedsilica gel chromatography (0-25% EtOAc in hexanes) to provide(2S)-2-(benzyloxy)-1-(4-fluorophenyl)propan-1-ol (1.404 g, 5.34 mmol,88% yield) as a colorless oil. ¹H NMR analysis showed the mixure to be a2:1 mixture of diastereomers. HRMS-ESI (m/z) [M+Na]+ calcd forC₁₆H₁₇FO₂Na, 283.1105; found, 283.1105.

Step 2: Preparation of (S)-2-(benzyloxy)-1-(4-fluorophenyl)propan-1-one.

A 100 mL round bottom flask was charged with CH₂Cl₂ (12.26 mL), andoxalyl chloride (0.519 mL, 5.93 mmol). This solution was cooled in a dryice/acetone bath under an atmosphere of N₂ and treated dropwise withDMSO (0.842 mL, 11.87 mmol). The resultant mixture was stirred for ˜2minutes and then treated dropwise with a solution of(2S)-2-(benzyloxy)-1-(4-fluorophenyl)propan-1-ol (1.404 g, 5.39 mmol) in3 mL of CH₂Cl₂ (extra rinse with 1 mL). After stirring for ˜15 minutes,the reaction mixture was treated dropwise with triethylamine (3.76 mL,27.0 mmol). The reaction mixture was stirred for 5 minutes and thenallowed to warm to room temperture. The reaction was monitored by TLC(20% EtOAc in hexanes). The reaction mixture was poured into H₂O and thephases were separated. The aqueous phase was extracted with CH₂Cl₂. Thecombined organics were dried with sodium sulfate and concentrated. Thecrude residue was purified by silica gel chromatography (0-15% EtOAc inhexanes) to provide (S)-2-(benzyloxy)-1-(4-fluorophenyl)propan-1-one(1.1475 g, 4.44 mmol, 82% yield) as a colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 8.20-8.04 (m, 2H), 7.40-7.24 (m, 5H), 7.19-7.02 (m, 2H), 4.70(q, J=6.9 Hz, 1H), 4.61 (d, J=11.6 Hz, 1H), 4.45 (d, J=11.6 Hz, 1H),1.54 (d, J=6.9 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ-104.39. ¹³C NMR (126MHz, CDCl₃) δ 199.27, 165.83 (d, J=255.3 Hz), 137.41, 131.69 (d, J=9.2Hz), 131.08 (d, J=2.9 Hz), 128.46, 127.98, 127.93, 115.71 (d, J=21.8Hz), 78.72, 71.65, 18.81. HRMS-ESI (m/z) [M+Na]+ calcd for C₁₆H₁₅FO₂Na,281.0948; found, 281.0950.

Step 2A: Preparation of (S)-1-(benzo[d][1,3]dioxol-5-yl)-2-(benzyloxy)propan-1-one.

To a vial charged with (S)-2-(benzyloxy)-1-(pyrrolidin-1-yl)propan-1-one(1 g, 4.29 mmol) dissolved in anhydrous THF (12 mL) was added dropwisebenzo[d][1,3]dioxol-5-ylmagnesium bromide (1M in 1:1 toluene/THF, 4.29mL, 4.29 mmol) at −5° C. The mixture was allowed to warm to ambienttemperature and stirred overnight. The mixture was quenched by theaddition of 1 N HCl. The layers were separated, followed by extractionwith ethyl ether (3×10 mL). The combined organic layers were washed withbrine, dried over sodium sulfate, and concentrated in vacuo. The residuewas purified via automated silica gel chromatography (Isco, 0-25%EtOAc/hexanes as the eluent) to afford(S)-1-(benzo[d][1,3]dioxol-5-yl)-2-(benzyloxy)propan-1-one (0.39 g, 30%)as yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.73 (dd, J=8.2, 1.7 Hz, 1H),7.55 (d, J=1.6 Hz, 1H), 7.39-7.27 (m, 5H), 6.84 (d, J=8.2 Hz, 1H), 6.04(s, 2H), 4.70 (q, J=6.9 Hz, 1H), 4.53 (dd, J=103.5, 11.6 Hz, 2H), 1.52(d, J=6.9 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 198.8, 152.0, 148.1,137.6, 129.4, 128.4, 127.9, 127.8, 125.2, 108.6, 107.9, 101.8, 78.4,71.5, 19.1. HRMS-ESI (m/z) [M+H]+ calcd for C₁₇H₁₇O₄, 285.1121; found,285.1121.

Step 3: Preparation of(2S)-2-(benzyloxy)-3-(4-fluorophenyl)-4-methylpentan-3-ol.

A solution of isopropylmagnesium bromide (1.936 mL, 3.87 mmol) was addedto anhydrous THF (6.45 ml) cooled to 0° C. in an ice bath. A solution of(S)-2-(benzyloxy)-1-(4-fluorophenyl)propan-1-one (0.5 g, 1.936 mmol) inTHF (2 mL+1 mL to rinse the syringe) was added dropwise. The reactionwas stirred until complete by consumption of starting material by TLC(20% EtOAc in hexanes). The reaction was quenched by the addition ofsaturated ammonium chloride and the mixture was extracted with EtOAc.The combined organic fractions were dried over MgSO₄, filtered andconcentrated. The crude residue was purified by automated silica gelchromatography (0-10% EtOAc in hexanes) to provide(2S)-2-(benzyloxy)-3-(4-fluorophenyl)-4-methylpentan-3-ol (201.9 mg,0.634 mmol, 33% yield) as a white foam. ¹H NMR data showed a 9.2:1 ratioof diastereomers. ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.20 (m, 7H), 7.00 (t,J=8.8 Hz, 2H), 4.72 (d, J=11.4 Hz, 1H), 4.49 (d, J=11.5 Hz, 1H), 4.09(q, J=6.2 Hz, 1H), 2.46 (s, 1H), 2.35 (p, J=6.8 Hz, 1H), 1.00 (d, J=6.2Hz, 3H), 0.77 (dd, J=8.8, 6.8 Hz, 6H). ¹⁹F NMR (376 MHz, CDCl₃)δ-117.13. ¹³C NMR (126 MHz, CDCl₃) δ 161.55 (d, J=244.4 Hz), 138.28,136.60 (d, J=3.2 Hz), 128.45, 128.14 (d, J=7.7 Hz), 127.80, 114.09 (d,J=20.9 Hz), 80.56, 70.91, 34.79, 17.93, 16.87, 13.63. HRMS-ESI (m/z)[M+Na]+ calcd for C₁₉H₂₃FO₂Na, 325.1574; found, 325.1574.

Step 4: Preparation of1-((2S,3S)-2-(benzyloxy)-4-methylpentan-3-yl)-4-fluorobenzene.

To a solution of(2S)-2-(benzyloxy)-3-(4-fluorophenyl)-4-methylpentan-3-ol (0.2 g, 0.661mmol) dissolved in CH₂Cl₂ (2.205 ml) at 0° C. was added triethylsilane(1.056 mL, 6.61 mmol) followed by trifluoroacetic acid (0.510 mL, 6.61mmol). The mixture was stirred at 0° C. for 1 hr. The mixture was thenallowed to slowly warm to room temperature and stirred overnight. Thereaction was carefully quenched by the addition of a saturated sodiumbicarbonate solution and extracted with CH₂Cl₂. The combined organiclayers were then dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude residue was purified by automatedsilica gel chromatography (0-5% EtOAc in hexanes) to provide1-((2S,3S)-2-(benzyloxy)-4-methylpentan-3-yl)-4-fluorobenzene (152.2 mg,0.505 mmol, 76% yield) as a colorless oil. ¹H NMR data revealed a 7.2:1ratio of diastereomers. ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.26 (m, 5H),7.07-6.91 (m, 4H), 4.66 (d, J=11.6 Hz, 1H), 4.50 (d, J=11.6 Hz, 1H),3.88 (dq, J=8.5, 6.1 Hz, 1H), 2.61 (d, J=14.4 Hz, 1H), 2.37 (dq, J=13.4,6.7 Hz, 1H), 1.01 (d, J=6.1 Hz, 3H), 0.80 (d, J=6.8 Hz, 3H), 0.74 (d,J=6.8 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 161.48 (d, J=243.8 Hz),138.84, 135.66 (d, J=3.3 Hz), 131.08 (d, J=7.6 Hz), 128.35, 127.71,127.49, 114.48 (d, J=20.8 Hz), 75.31, 70.71, 57.21, 27.57, 21.59, 18.36,17.35. HRMS-ESI (m/z) [M+Na]+ calcd for C₁₉H₂₃FONa, 309.1625; found,309.1629.

Step 5: Preparation of (2S,3S)-3-(4-fluorophenyl)-4-methylpentan-2-ol.

A flask containing1-((2S)-2-(benzyloxy)-4-methylpentan-3-yl)-4-fluorobenzene (0.15 g,0.524 mmol) was charged with 5% palladium on carbon (0.056 g, 0.026mmol) and then suspended in ethanol (2.62 mL). The reaction atmospherewas replaced with hydrogen gas via a balloon (1 atm) and montinoreduntil complete by TLC (25% EtOAc in hexanes). The reaction was filteredthrough a pad of Celite© and the pad was washed with ethyl acetate. Thefiltrate was concentrated under reduced pressure. The crude residue waspurified by automated column chromatography (0-20% EtOAc in hexanes asthe eluent) to provide (2S,3S)-3-(4-fluorophenyl)-4-methylpentan-2-ol(76.9 mg, 0.388 mmol, 74.1% yield) as a white foam. ¹H NMR (500 MHz,CDCl₃) d 7.11-7.05 (m, 2H), 7.03-6.97 (m, 2H), 4.17 (dq, J=7.5, 6.2 Hz,1H), 2.47 (t, J=7.5 Hz, 1H), 2.18 (dp, J=13.6, 6.8 Hz, 1H), 1.19 (d,J=7.2 Hz, 1H), 1.03 (d, J=6.3 Hz, 3H), 0.90 (d, J=6.7 Hz, 3H), 0.79 (d,J=6.7 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 161.65 (d, J=244.4 Hz), 135.15(d, J=3.4 Hz), 131.11 (d, J=7.6 Hz), 114.76 (d, J=20.9 Hz), 68.13,59.08, 28.28, 21.34, 20.53, 19.47. IR (thin film) 3348, 2960, 2929,2872, 1604, 1508, 1465, 1368, 1223, 1160, 833 cm⁻¹.

Step 6: Preparation of(4S)-4-(benzyloxy)-3-(4-fluorophenyl)-2-methylpent-1-en-3-ol.

To a solution containing prop-1-en-2-ylmagnesium bromide (1 M in2-Me-THF) (4.29 mL, 4.29 mmol) dissolved in THF (21.44 mL) and cooled to0° C. in an ice/water bath was added(S)-2-(benzyloxy)-1-(4-fluoro-3-methylphenyl)propan-l-one (0.584 g,2.144 mmol) dropwise over 5 minutes as a solution in THF (3 mL). Theresulting solution was stirred for 1 hr, at which point an additional2.1 mL (1 equivalent) of the Grignard reagent was added, and thereaction was stirred for an additional hour. The reaction was quenchedwith saturated aqueous NH₄Cl (50 mL) solution and extracted with EtOAc(3×50 mL). The combined organic layers were dried over Na₂SO₄, filtered,and concentrated to an oil. The oil was loaded onto a prepacked 25 gsilica gel column and purified using Isco silica gel columnchromatography (40 column, 35 mL/min, 100% hexanes to 20% ethylacetate:hexanes) to afford the title compound (671 mg, 100%) as a clear,colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.23 (m, 6H), 7.16 (ddd,J=7.9, 4.9, 2.4 Hz, 1H), 6.92 (t, J=9.0 Hz, 1H), 5.17 (t, J=1.0 Hz, 1H),4.98 (p, J=1.4 Hz, 1H), 4.69 (d, J=11.4 Hz, 1H), 4.51 (d, J=11.4 Hz,1H), 4.21 (q, J=6.1 Hz, 1H), 2.81 (s, 1H), 2.26 (d, J=1.9 Hz, 3H), 1.63(t, J=1.0 Hz, 3H), 0.99 (d, J=6.1 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃)d-120.68. IR (thin film) 3500, 2977, 2923, 1499, 1242, 1114, 1097, 894,818, 733, 697 cm⁻¹. HRMS-ESI (m/z) [M+H]+ calcd for C₂₀H₂₃FNaO₂,337.1574; found, 337.1584.

Step 7: Preparation of(2S)-2-(benzyloxy)-3-(4-fluorophenyl)-4-methylpentan-3-ol.

A solution containing(3S,4S)-4-(benzyloxy)-3-(4-fluoro-3-methylphenyl)-2-methylpent-1-en-3-ol(0.6713 g, 2.135 mmol) and Wilkinson's catalyst (0.593 g, 0.641 mmol)dissolved in THF (14.23 mL) was flushed with hydrogen gas via balloon.The resulting reaction was stirred at room temperature overnight. Thereaction mixture was concentrated to a dark orange-brown oil underreduced pressure. The resulting oil was loaded directly onto a 25 gprepacked silica column in a minimal amount of dichloromethane andpurified using Isco silica gel column chromatography (40 column, 35mL/min, 100% hexanes to 20% ethyl acetate:hexanes) to afford the titlecompound (659 mg, 98%) as a clear, colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 7.41-7.28 (m, 5H), 7.16 (dd, J=7.6, 2.3 Hz, 1H), 7.05 (ddd,J=7.8, 5.0, 2.4 Hz, 1H), 6.92 (t, J=9.0 Hz, 1H), 4.72 (d, J=11.4 Hz,1H), 4.49 (d, J=11.4 Hz, 1H), 4.08 (q, J=6.2 Hz, 1H), 2.44 (s, 1H), 2.34(p, J=6.8 Hz, 1H), 2.27 (d, J=1.9 Hz, 3H), 1.01 (d, J=6.1 Hz, 3H), 0.77(dd, J=10.6, 6.8 Hz, 6H). ¹⁹F NMR (376 MHz, CDCl₃) δ-121.44. ¹³C NMR(101 MHz, CDCl₃) δ 160.12 (d, J=243.5 Hz), 138.39, 136.31 (d, J=3.5 Hz),129.74 (d, J=4.9 Hz), 128.45, 127.79, 127.75, 125.35 (d, J=7.8 Hz),123.40 (d, J=17.0 Hz), 113.69 (d, J=22.1 Hz), 80.55, 77.07, 70.95,34.84, 18.01, 16.94, 14.80 (d, J=3.5 Hz), 13.71. IR (thin film) 3564,2962, 2935, 1501, 1374, 1243, 1105, 1089, 817, 757, 697 cm⁻¹. HRMS-ESI(m/z) [M+H]+ calcd for C₂₀H₂₅FNaO₂, 339.1731; found, 339.1728.

Example 6A: Preparation of(2R,3S)-3-(2,5-dimethylphenyl)-4-methylpentan-2-ol

Step 1: Preparation of 2-(2,5-dimethylphenyl)-3-methylbutanoic acid.

A solution of isopropylmagnesium chloride (2 M in THF, 5.79 mL, 11.57mmol) was added slowly to a solution of 2-(2,5-dimethylphenyl)aceticacid (0.95 g, 5.79 mmol) in THF (11.57 mL) at room temperature. Theresulting thick suspension was stirred for 1 hr and treated with2-iodopropane (1.736 mL, 17.36 mmol). The reaction was heated to 70° C.and stirred overnight. The reaction was quenched by the addition of 1NHCl and extracted with EtOAc. The organic layer was dried over magnesiumsulfate, filtered and concentrated under reduced pressure. Theresiduewas purified by automated column chromatography (Isco, 0-30%EtOAc in hexanes as the eluent) to provide2-(2,5-dimethylphenyl)-3-methylbutanoic acid (670 mg, 53.3%) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ 11.32 (bs, 1H), 7.21 (s, 1H), 7.04 (d,J=7.7 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H), 3.46 (d, J=10.9 Hz, 1H),2.40-2.34 (m, 1H), 2.33 (s, 3H), 2.29 (s, 3H), 1.11 (d, J=6.4 Hz, 3H),0.69 (d, J=6.7 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 179.72, 136.08,135.79, 133.69, 130.22, 127.82, 127.67, 54.23, 31.46, 21.62, 21.12,19.75, 19.69. HRMS-ESI (m/z) [2M+H]+ calcd for C₁₃H₁₈O₂, 413.2686;found, 413.2674.

Step 2: Preparation of2-(2,5-dimethylphenyl)-N-methoxy-N,3-dimethylbutanamide.

To a solution containing 2-(2,5-dimethylphenyl)-3-methylbutanoic acid(0.66 g, 3.20 mmol) dissolved in 32 mL of CH₂Cl₂ at 0° C. was added4-methylmorpholine (0.70 mL, 6.40 mmol) and N,O-dimethylhydroxylaminehydrochloride (0.624 g, 5.71 mmol).3-(((Ethylimino)methylene)amino)-N,N-dimethylpropan-1-aminehydrochloride (EDC, 1.23 g, 6.40 mmol) was added and the reaction waswarmed to room temperature and stirred overnight. The reaction wasconcentrated under reduced pressure and the residue was purified byautomated silica gel chromatography (Isco, 0-25% EtOAc in hexanes as theeluent) to provide2-(2,5-dimethylphenyl)-N-methoxy-N,3-dimethylbutanamide (694 mg, 83%) asa colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.27 (s, 1H), 7.01 (d, J=7.7Hz, 1H), 6.93-6.89 (m, 1H), 3.84 (d, J=10.3 Hz, 1H), 3.48 (s, 3H), 3.14(s, 3H), 2.41-2.35 (m, 1H), 2.34 (s, 3H), 2.27 (s, 3H), 1.05 (d, J=6.4Hz, 3H), 0.68 (d, J=6.8 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 137.49,135.69, 133.14, 129.89, 127.88, 127.23, 60.95, 49.90, 32.65, 32.21,22.25, 21.11, 19.51. HRMS-ESI (m/z) [M+H]+ calcd for C₁₅H₂₃NO₂,250.1802; found, 250.1799.

Step 3: Preparation of 3-(2,5-dimethylphenyl)-4-methylpentan-2-one.

A solution containing2-(2,5-dimethylphenyl)-N-methoxy-N,3-dimethylbutanamide (0.685 g, 2.75mmol) dissolved in THF (18.31 mL) was cooled to 0° C. Methylmagnesiumbromide (3.0 M in diethyl ether, 2.75 ml, 8.24 mmol) was added dropwiseand the reaction was allowed to warm to room temperature and stirredovernight. The reaction was quenched by the addition of saturatedammonium chloride solution and was extracted with EtOAc. The organiclayer was dried over magnesium sulfate, filtered and concentrated underreduced pressure to provide 3-(2,5-dimethylphenyl)-4-methylpentan-2-one(573.3 mg, 97%) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.27 (s, 1H),7.06 (d, J=7.6 Hz, 1H), 6.94 (d, J=7.7 Hz, 1H), 3.58 (d, J=10.5 Hz, 1H),2.44-2.38 (m, 1H), 2.37 (s, 3H), 2.27 (s, 3H), 2.02 (s, 3H), 1.01 (d,J=6.4 Hz, 3H), 0.65 (d, J=6.8 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ208.55, 136.24, 135.95, 133.52, 130.48, 127.83, 127.61, 62.29, 30.53,30.09, 21.86, 21.04, 19.91, 19.51. HRMS-ESI (m/z) [M+H]+ calcd forC₁₄H₂₀O, 205.1587; found, 205.1578.

Step 4: Preparation of(2R,3S)-3-(2,5-dimethylphenyl)-4-methylpentan-2-ol and(2S,3R)-3-(2,5-dimethylphenyl)-4-methylpentan-2-ol.

Lithium aluminum hydride (2.80 mL, 2.80 mmol) as a solution (1.0 M inTHF) was added to a flask containing THF (28.0 mL) cooled to −78° C. Asolution of 3-(2,5-dimethylphenyl)-4-methylpentan-2-one (0.573 g, 2.80mmol) in THF (3 mL) was added dropwise. The reaction was warmed to roomtemperature and stirred overnight. The reaction was cooled to 0° C. andquenched by the addition of 0.1 mL H₂O, 0.1 mL 1N NaOH, followed by anadditional 0.3 mL of H₂O. The mixture was stirred vigorously for 15 min.The reaction was filtered and the solids were washed with EtOAc. Thefiltrate was concentrated under reduced pressure to provide a racemicmixture of (2R,3S)-3-(2,5-dimethylphenyl)-4-methylpentan-2-ol and(2S,3R)-3-(2,5-dimethylphenyl)-4-methylpentan-2-ol (491 mg, 72%) as acolorless oil. The syn product is the exclusive product as predicted byCram's rule. ¹H NMR (500 MHz, CDCl₃) δ 7.12 (s, 1H), 7.05 (d, J=7.7 Hz,1H), 6.94-6.91 (m, 1H), 4.32-4.20 (m, 1H), 2.55 (dd, J=8.9, 4.7 Hz, 1H),2.31 (s, 3H), 2.25 (s, 3H), 2.17 (ddt, J=13.3, 8.8, 6.7 Hz, 1H), 1.26(d, J=6.1 Hz, 1H), 1.05 (d, J=2.3 Hz, 3H), 1.04 (d, J=2.0 Hz, 3H), 0.72(d, J=6.7 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 138.84, 135.13, 134.66,130.18, 128.14, 126.71, 67.91, 62.20, 53.16, 30.01, 21.76, 21.36, 20.75,20.29. ESIMS (m/z) 207 [M+H]⁺.

Step 5: Preparation of (2R,3S) and(2S,3R)-3-(2,5-dimethylphenyl)-4-methylpentan-2-yl(S)-2-methoxy-2-phenylacetate.

To a racemic mixture containing (2R,3S) and(2S,3R)-3-(2,5-dimethylphenyl)-4-methylpentan-2-ol (0.491 g, 2.380 mmol)dissolved in 16 mL of CH₂Cl₂ was added N,N-dimethylpyridin-4-amine(0.029 g, 0.238 mmol) and (S)-2-methoxy-2-phenylacetic acid (0.514 g,3.09 mmol). The reaction was cooled to 0° C. followed by addition of3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-aminehydrochloride (0.912 g, 4.76 mmol) was added and the reaction was warmedto room temperature and stirred overnight. The mixture was concentratedunder reduced pressure. The residue was purified by automated silica gelchromatography (Isco, 80 g SiO₂ column, 0-10% MTBE in hexanes as theeluent) to provide (2R,3S)-3-(2,5-dimethylphenyl)-4-methylpentan-2-yl(S)-2-methoxy-2-phenylacetate (284.7 mg 32%) and(2S,3R)-3-(2,5-dimethylphenyl)-4-methylpentan-2-yl(S)-2-methoxy-2-phenylacetate as colorless oils. Only the desired(2R,3S) diastereomer was characterized. ¹H NMR (500 MHz, CDCl₃) δ7.44-7.37 (m, 2H), 7.36-7.27 (m, 3H), 7.18 (s, 1H), 7.00 (d, J=7.7 Hz,1H), 6.93-6.80 (m, 1H), 5.42-5.34 (m, 1H), 4.74 (s, 1H), 3.40 (s, 3H),2.62 (dd, J=9.7, 4.3 Hz, 1H), 2.30 (s, 3H), 2.21 (s, 3H), 2.05-1.92 (m,1H), 0.93 (d, J=6.5 Hz, 3H), 0.87 (d, J=6.3 Hz, 3H), 0.68 (d, J=6.7 Hz,3H). ¹³C NMR (126 MHz, CDCl₃) δ 170.32, 139.03, 136.46, 134.96, 133.92,129.67, 128.80, 128.51, 126.90, 126.67, 82.86, 72.23, 57.31, 51.06,30.54, 21.31, 21.00, 20.93, 20.23, 17.82. HRMS-ESI (m/z) [M+Na]+ calcdfor C₂₃H₃₀O₃, 377.2087; found, 377.2089.

Step 6: Preparation of(2R,3S)-3-(2,5-dimethylphenyl)-4-methylpentan-2-ol.

To a solution containing(2R,3S)-3-(2,5-dimethylphenyl)-4-methylpentan-2-yl(S)-2-methoxy-2-phenylacetate(0.28 g, 0.790 mmol) dissolved in MeOH (7.90 mL) was added potassiumcarbonate (0.327 g, 2.370 mmol). The reaction was heated to 55° C. andstirred overnight. The reaction was cooled to room temperature, dilutedwith water and extracted with CH₂Cl₂. The combined organic layers weredried over sodium sulfate, filtered and concentrated under reducedpressure. The crude material was purified by automated silica gelchromatography (Isco, 0-20% EtOAc in hexanes as the eluent) to provide(2R,3S)-3-(2,5-dimethylphenyl)-4-methylpentan-2-ol (139 mg, 81%) as acolorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.12 (s, 1H), 7.05 (d, J=7.7Hz, 1H), 6.96-6.87 (m, 1H), 4.33-4.19 (m, 1H), 2.55 (dd, J=8.9, 4.7 Hz,1H), 2.31 (s, 3H), 2.25 (s, 3H), 2.17 (ddt, J=13.4, 8.8, 6.7 Hz, 1H),1.26 (d, J=6.1 Hz, 1H), 1.05 (d, J=2.1 Hz, 3H), 1.04 (d, J=1.8 Hz, 3H),0.72 (d, J=6.7 Hz, 3H). IR (thin film) 3429 (b), 2956, 2925, 2868, 1500,1457, 1382, 1151, 1027, 905, 806, 787 cm⁻¹. HRMS-ESI (m/z) [M+NH4]+calcd for C₁₄H₂₂O, 224.2009; found, 224.2001.

Example 7: Preparation of(2S,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-ol

Step 1: Preparation of(2S,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-yl4-nitrobenzoate.

In a 250 mL round bottom flask, a solution of(2R,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-ol (0.880 g, 4.18mmol), triphenylphosphine (4.17 g, 15.90 mmol) and 4-nitrobenzoic acid(2.87 g, 17.16 mmol) was prepared in anhydrous THF (41.8 ml) and cooledto 0° C. in an ice/water bath. After ˜5 min, diethyl(E)-diazene-1,2-dicarboxylate (2.97 ml, 18.83 mmol) was added dropwise,and the mixture was allowed to slowly warm to room temperatureovernight. After 18 hr, TLC indicated ˜75% conversion to a single higherRf spot. The reaction was then heated to 40° C. and stirred for anadditional 12 hr. The mixture was cooled to room temperature andquenched with a saturated aqueous solution of NH₄Cl (40 mL) andextracted with CH₂Cl₂ (3×40 mL). The combined organic layers were passedthrough a phase separator and concentrated to an oil. The residue waspurified via silica gel Isco column chromatography (80 g silica gelcolumn, 60 mL/min, 100% hexanes to 20% acetone:hexanes) to afford(2S,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-yl4-nitrobenzoate(1.34 g, 3.73 mmol, 89% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃)δ 8.33-8.26 (m, 2H), 8.17-8.11 (m, 2H), 7.14 (dd, J=9.5, 5.9 Hz, 1H),6.98-6.86 (m, 2H), 5.65 (dq, J=8.2, 6.3 Hz, 1H), 3.18 (t, J=7.8 Hz, 1H),2.30 (s, 3H), 2.19-2.09 (m, 1H), 1.19 (d, J=6.3 Hz, 3H), 0.98 (d, J=6.7Hz, 3H), 0.80 (d, J=6.8 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ-117.11. IR(thin film) 3353, 2961, 1719, 1528, 1277, 1102, 720 cm⁻¹. ESIMS (m/z)359.1 [M+H]⁺.

Step 2: Preparation of(2S,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-ol.

In a 250 mL round-bottom flask, a solution of(2S,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-yl 4-nitrobenzoate(1.34 g, 3.73 mmol) was prepared in THF (49.7 mL) and cooled to 0° C. inan ice/water bath. After ˜5 min, sodium hydroxide (10% aqueous solution)(44 mL, 3.73 mmol) (39.7 mL water+4.4 mL 50% w/w/NaOH) was addeddropwise, and the mixture was allowed to slowly warm to room temperatureover 1 hr and then heated to 40° C. and stirred for 2 days. The reactionwas cooled to ambient temperature. The reaction was quenched by theaddition of a saturated aqueous solution of NH₄Cl (100 mL) and extractedwith CH₂Cl₂ (3×100 mL). Additional product remained in aqueous layer asevidenced by TLC, so 100 mL brine was added to aqueous layer, and theaqueous layer was extracted again with CH₂Cl₂ (2×100 mL), after which noadditional product was observed in the aqueous layer. The combinedorganic layers were then passed through a phase separator andconcentrated to afford an oil that was purified via silica gel Iscocolumn chromatography (120 g silica gel column, 85 mL/min, 100% hexanesto 30% acetone:hexanes) to afford(2S,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-ol (460 mg, 2.187mmol, 58.7% yield) (52% over 2 steps) as a clear, colorless oil. ¹H NMR(400 MHz, CDCl₃) δ7.02 (dd, J=8.6, 6.0 Hz, 1H), 6.94-6.81 (m, 2H),4.25-4.12 (m, 1H), 2.88 (t, J=7.6 Hz, 1H), 2.35 (s, 3H), 2.25-2.12 (m,1H), 1.21 (d, J=6.0 Hz, 1H), 1.04 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.7 Hz,3H), 0.80 (d, J=6.7 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ-117.86. ¹³C NMR(101 MHz, CDCl₃) d 160.86 (d, J=243.9 Hz), 140.35 (d, J=7.4 Hz), 134.42(d, J=3.1 Hz), 129.29 (d, J=6.8 Hz), 116.88 (d, J=20.3 Hz), 112.20 (d,J=20.6 Hz), 69.48, 29.72, 21.12, 21.00, 20.99, 20.65, 19.98. IR (thinfilm) 3382, 2960, 2927, 1716, 1497, 1365, 1225, 736 cm⁻¹.

Example 8:(2S,3S)-3-(4-fluorophenyl)-4-methylpentan-2-yl(tert-butoxycarbonyl)-L-alaninate

To a stirred solution of (2S,3S)-3-(4-fluorophenyl)-4-methylpentan-2-ol(0.075 g, 0.382 mmol), (tert-butoxycarbonyl)-L-alanine (0.108 g, 0.573mmol) and DMAP (4.67 mg, 0.038 mmol) dissolved in CH₂Cl₂ (3.82 mL) at 0°C. in an ice bath was addedN¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (EDC; 0.147 g, 0.764 mmol) and the reaction was monitoreduntil complete by TLC (25% EtOAc in hexanes). The reaction was purifiedby automated column chromatography (0-10% EtOAc in hexanes) to provide(2S,3S)-3-(4-fluorophenyl)-4-methylpentan-2-yl(tent-butoxycarbonyl)-L-alaninate (137.5 mg, 0.370 mmol, 97% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.06 (dd, J=8.7, 5.6 Hz, 2H),7.02-6.92 (m, 2H), 5.36 (dq, J=8.7, 6.3 Hz, 1H), 5.05 (s, 1H), 4.37-4.19(m, 1H), 2.69 (dd, J=8.7, 6.4 Hz, 1H), 2.08 (h, J=6.7 Hz, 1H), 1.45 (s,9H), 1.38 (d, J=7.2 Hz, 3H), 1.06 (d, J=6.2 Hz, 3H), 0.86 (d, J=6.8 Hz,3H), 0.74 (d, J=6.8 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 172.79 , 161.75(d, J=244.8 Hz), 155.03, 134.29, 131.03 (d, J=7.6 Hz), 114.82 (d, J=21.0Hz), 79.79, 72.32, 55.88, 49.50, 28.34, 28.18, 21.30, 18.81, 18.41,17.74. IR (thin film) 3352, 2964, 2932, 1712, 1605, 1509, 1452, 1366,1224, 1160, 835 cm⁻¹. HRMS-ESI (m/z) [M+Na]+ calcd for C₂₀H₃₀FNNaO₄,390.2051; found, 390.2044.

Example 9: Preparation of(2S,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-yl(tent-butoxycarbonyl)-L-alaninate

In a small vial, (2R,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-ol(115.5 mg, 0.549 mmol), (tent-butoxycarbonyl)-L-alanine (125 mg, 0.659mmol) and triphenylphosphine (173 mg, 0.659 mmol) were dissolved in THF(2.75 mL) under a N₂ atmosphere and cooled to 0° C. in an ice/waterbath. After ˜5 min, diisopropyl (E)-diazene-1,2-dicarboxylate (130 μL,0.659 mmol) was added in dropwise via syringe over 3 min, and theresulting pale orange reaction was stirred overnight, slowly warming toroom temperature as the ice melted. After 18 hr, the reaction wasconcentrated under reduced pressure to afford an oil. The oil was loadeddirectly onto a 12 g prepacked silica column in a minimal amount ofdichloromethane and purified using Isco silica gel column chromatography(120 column, 85 mL/min, 100% pet ether to 40% MTBE:pet ether) to afford(2S,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-yl(tent-butoxycarbonyl)-L-alaninate (35.0 mg, 0.092 mmol, 17% yield) as aclear, colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.05 (dd, J=8.5, 6.0 Hz,1H), 6.87 (ddt, J=11.6, 8.3, 4.1 Hz, 2H), 5.33 (dq, J=9.1, 6.2 Hz, 1H),5.05 (d, J=8.1 Hz, 1H), 4.28 (d, J=7.6 Hz, 1H), 3.08 (dd, J=9.2, 6.2 Hz,1H), 2.32 (s, 3H), 2.18-2.06 (m, 1H), 1.45 (s, 9H), 1.39 (d, J=7.2 Hz,3H), 1.03 (d, J=6.2 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H), 0.78 (d, J=6.9 Hz,3H). ¹⁹F NMR (376 MHz, CDCl₃) δ-117.34. IR (thin film) 3355, 2965, 1714,1499, 1366, 1167, 1052, 735 cm⁻¹. HRMS-ESI (m/z) [M+Na]+ calcd forC₂₁H₃₂FNNaO₄, 404.2208; found, 404.2201.

Example 10: Preparation of(2S,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-yl(3-hydroxy-4-methoxypicolinoyl)-L-alaninate

Step 1: Preparation of(2S,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-yl-L-alaninatehydrochloride.

In a small vial,(2S,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-yl-(tert-butoxycarbonyl)-L-alaninate(35.0 mg, 0.092 mmol) was dissolved in CH₂Cl₂ (2 mL). Hydrogen chloride(4M in dioxane) (0.344 mL, 1.376 mmol) was added in one portion viasyringe. The resulting clear, colorless reaction was stirred at roomtemperature for 3 hr. After 3 hr, TLC indicated complete consumption ofthe starting material and conversion to a baseline product by TLC. Thereaction was concentrated under a stream of N₂ and dried in a vacuumoven to provide(2S,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-yl-L-alaninate(26.1 mg, 0.092 mmol, 100% yield) as a clear, colorless oil. ESIMS (m/z)282.1 [M+H]⁺. This material was used directly in the next step withoutfurther purification.

Step 2: Preparation of(2S,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-yl(3-hydroxy-4-methoxypicolinoyl)-L-alaninate.

To a vial containing(2S,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-yl-L-alaninate(26.1 mg, 0.093 mmol) was added 3-hydroxy-4-methoxypicolinic acid (23.53mg, 0.139 mmol) and((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tri(pyrrolidin-1-yl)phosphoniumhexafluorophosphate(V) (72.4 mg, 0.139 mmol). Dichloromethane (1.86 mL)was added followed by N-ethyl-N-isopropylpropan-2-amine (121 μL, 0.696mmol) dropwise over 45 seconds. After 10 min, most of the solidssolubilized and the resultant pale pink colored reaction was stirred atroom temperature overnight. TLC/UPLC indicated consumption of thestarting material and formation of a major spot that glowed blue underUV. The reaction was then concentrated under reduced pressure to yieldan orange oil. The oil was loaded directly onto a 12 g prepacked silicacolumn in a minimal amount of dichloromethane and purified using Iscosilica gel column chromatography (24 column, 30 mL/min, 100% hexanes to50% acetone : hexanes) to afford(2S,3S)-3-(4-fluoro-2-methylphenyl)-4-methylpentan-2-yl-(3-hydroxy-4-methoxypicolinoyl)-L-alaninate (24.4 mg, 0.056 mmol, 60.8% yield) as a clear, colorlessoil. ¹H NMR (400 MHz, CDCl₃) δ 12.13 (s, 1H), 8.45 (d, J=8.0 Hz, 1H),7.99 (d, J=5.2 Hz, 1H), 7.05 (dd, J=8.6, 5.9 Hz, 1H), 6.93-6.77 (m, 3H),5.38 (dq, J=8.9, 6.3 Hz, 1H), 4.76-4.65 (m, 1H), 3.95 (s, 3H), 3.09 (dd,J=8.9, 6.5 Hz, 1H), 2.29 (s, 3H), 2.11 (h, J=6.8 Hz, 1H), 1.55 (d, J=7.2Hz, 3H), 1.08 (d, J=6.2 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H), 0.78 (d, J=6.7Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ-117.30. IR (thin film) 3366, 2961,1734, 1650, 1529, 1264, 1183, 1049, 955, 801, 735 cm⁻¹. HRMS-ESI (m/z)[M+H]+ calcd for C₂₃H₃₀FN₂O₅, 433.2133; found, 433.2129.

Example 11A: Preparation of(2S,3R)-3-(2,4-dimethylphenyl)-4-methylpentan-2-yl(3-acetoxy-4-methoxypicolinoyl)-L-alaninate

To a 20 mL vial charged with(2S,3R)-3-(2,4-dimethylphenyl)-4-methylpentan-2-yl(3-hydroxy-4-methoxypicolinoyl)-L-alaninate (30 mg, 0.070 mmol)dissolved in pyridine (1 mL, 12.36 mmol) was added acetic anhydride (25μL, 2.65 mmol) at room temperature. After stirring for 45 min, themixture was concentrated in vacuo and purified via automated silica gelchromatography (0-40% acetone/hexanes as the eluent) to afford(2S,3R)-3-(2,4-dimethylphenyl)-4-methylpentan-2-yl(3-acetoxy-4-methoxypicolinoyl)-L-alaninate (32 mg, 0.061 mmol, 87%yield) as colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 8.56 (s, 1H), 8.35(d, J=5.4 Hz, 1H), 7.19 (d, J=7.9 Hz, 1H), 7.00 (d, J=5.4 Hz, 1H), 6.94(d, J=1.9 Hz, 1H), 6.90 (dd, J=7.9, 1.9 Hz, 1H), 5.41 (qd, J=6.3, 4.7Hz, 1H), 4.77-4.61 (m, 1H), 3.91 (s, 3H), 2.68 (dd, J=9.3, 4.8 Hz, 1H),2.39 (s, 3H), 2.27 (s, 3H), 2.25 (s, 3H), 2.03 (dp, J=9.2, 6.6 Hz, 1H),1.38 (d, J=7.2 Hz, 3H), 1.05 (d, J=6.3 Hz, 3H), 0.99 (d, J=6.6 Hz, 3H),0.69 (d, J=6.8 Hz, 3H). IR (thin film) 3383, 2969, 1772, 1733, 1679,1200, 1176 cm⁻¹. HRMS-ESI (m/z) [M+H]+ calcd for C₂₆H₃₅N₂O₆, 471.2490;found, 471.2485.

Example 11B: Preparation of(2S,3R)-3-(2,4-dimethylphenyl)-4-methylpentan-2-yl(3-(acetoxymethoxy)-4-methoxypicolinoyl)-L-alaninate

To a 20 mL vial charged with in(2S,3R)-3-(2,4-dimethylphenyl)-4-methylpentan-2-yl(3-hydroxy-4-methoxypicolinoyl)-L-alaninate (30 mg, 0.070 mmol) andpotassium carbonate (19.35 mg, 0.140 mmol) dissolved in acetone (1.5 mL)was added bromomethyl acetate (0.014 mL, 0.140 mmol) at roomtemperature. After stirring for 2 hr at 50° C., the mixture wasconcentrated in vacuo and purified via automated silica gelchromatography (0-40% acetone/hexanes as the eluent) to afford(2S,3R)-3-(2,4-dimethylphenyl)-4-methylpentan-2-yl(3-(acetoxymethoxy)-4-methoxypicolinoyl)-L-alaninate(21 mg, 0.038 mmol, 54% yield) as colorless oil. ¹H NMR (500 MHz, CDCl₃)δ 8.38 (d, J=7.9 Hz, 1H), 8.29 (d, J=5.4 Hz, 1H), 7.20 (d, J=7.9 Hz,1H), 7.00-6.87 (m, 3H), 5.80-5.69 (m, 2H), 5.42 (qd, J=6.2, 4.7 Hz, 1H),4.71 (p, J=7.2 Hz, 1H), 3.91 (s, 3H), 2.69 (dd, J=9.2, 4.9 Hz, 1H), 2.27(s, 3H), 2.25 (s, 3H), 2.10-1.97 (m, 1H), 2.06 (s, 3H), 1.39 (d, J=7.2Hz, 3H), 1.07 (d, J=6.3 Hz, 3H), 0.99 (d, J=6.6 Hz, 3H), 0.70 (d, J=6.7Hz, 3H). IR (thin film) 3380, 2969, 1732, 1675, 1502, 1200, 1003, 967,829 cm⁻¹. HRMS-ESI (m/z) [M+H]+ calcd for C₂₇H₃₇N₂O₇, 501.2595; found,501.2589.

Example 11C: Preparation of(2S,3S)-3-(3-fluoro-4-methoxyphenyl)-4-methylpentan-2-yl(4-methoxy-3-((3-methoxypropanoyl)oxy)picolinoyl)-L-alaninate

To a stirred solution of(2S,3S)-3-(3-fluoro-4-methoxyphenyl)-4-methylpentan-2-yl(3-hydroxy-4-methoxypicolinoyl)-L-alaninate (59.3 mg, 0.132 mmol) and4-(dimethylamino)pyridine (3.23 mg, 0.026 mmol) dissolved in CH₂Cl₂ (2.0mL) was added triethylamine (0.037 mL, 0.264 mmol) followed by3-methoxypropanoyl chloride (0.022 mL, 0.198 mmol). The reaction wasallowed to stir at room temperature overnight. The reaction wasconcentrated under a stream of nitrogen. The residue was loaded directlyonto a 12 g prepacked silica column in a minimal amount ofdichloromethane and purified using Isco silica gel column chromatography(24 g column, 35 mL/min, 100% hexanes to 50% acetone:hexanes as theeluent) to afford the title compound (58.5 mg, 83% yield) as a paleyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (d, J=7.9 Hz, 1H), 8.34 (d,J=5.4 Hz, 1H), 7.01 (d, J=5.5 Hz, 1H), 6.92-6.75 (m, 3H), 5.34 (dq,J=8.3, 6.2 Hz, 1H), 4.66 (dt, J=8.1, 7.1 Hz, 1H), 3.90 (s, 3H), 3.86 (s,3H), 3.81 (t, J=6.6 Hz, 2H), 3.40 (s, 3H), 2.99 (t, J=6.6 Hz, 2H), 2.64(dd, J=8.6, 6.5 Hz, 1H), 2.05 (h, J=6.8 Hz, 1H), 1.49 (d, J=7.2 Hz, 3H),1.09 (d, J=6.3 Hz, 3H), 0.87 (d, J=6.7 Hz, 3H), 0.75 (d, J=6.7 Hz, 3H).¹³C NMR (101 MHz, CDCl₃) δ 172.19, 169.42, 162.36, 159.51, 151.94 (d,J=245.0 Hz), 146.73, 146.25 (d, J=10.8 Hz), 141.62, 137.42, 131.84 (d,J=5.6 Hz), 125.47 (d, J=3.6 Hz), 117.15 (d, J=18.2 Hz), 113.05-112.84(m), 109.77, 72.51, 67.62, 58.76, 56.33, 56.24, 55.74, 48.21, 34.67,28.35, 21.25, 18.77, 18.63, 17.47. ¹⁹F NMR (376 MHz, CDCl₃) δ-135.76.HRMS-ESI (m/z) [M+H]⁺ calcd for C₂₇H₃₆FN₂O₈, 535.2450; found, 535.2444.

Example 12: Preparation of(1R,2S)-1-cyclopentyl-1-phenylpropan-2-yl(3-acetoxy-4-methoxypyridine-2-carbonothioyl)-L-alaninate

Step 1: Preparation of (1R,2S)-1-cyclopentyl-1-phenylpropan-2-yl(3-hydroxy-4-methoxypyridine-2-carbonothioyl)-L-alaninate.

To a 30 mL vial charged with (1R,2S)-1-cyclopentyl-1-phenylpropan-2-yl(3-hydroxy-4-methoxypicolinoyl)-L-alaninate (99 mg, 0.232 mmol)dissolved in acetonitrile (2.32 mL) was added phosphorous pentasulfide(103 mg, 0.464 mmol) and 1,1,1,3,3,3-hexamethyldisiloxane (248 μL, 1.161mmol). After stirring for 45 min at 45° C., sat. NaHCO₃ (15 mL) wasadded followed by aqueous extraction with dichloromethane (3×15 mL). Theorganics were dried over MgSO₄, filtered, and concentrated in vacuo. Thecrude residue was purified via flash chromatography (0-45%acetone/hexanes as the eluent) to furnish(1R,2S)-1-cyclopentyl-1-phenylpropan-2-yl(3-hydroxy-4-methoxypyridine-2-carbonothioyl)-L-alaninate (72 mg, 0.155mmol, 66.6% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 12.94 (s,1H), 10.71 (s, 1H), 8.01 (d, J=15.0 Hz, 1H), 7.22-7.17 (m, 3H), 7.15(dd, J=6.7, 3.0 Hz, 2H), 6.89 (d, J=5.0 Hz, 1H), 5.39 (qd, J=6.4, 4.0Hz, 1H), 5.12-5.03 (m, 1H), 3.97 (s, 3H), 2.41 (dd, J=10.4, 4.0 Hz, 1H),2.25-2.14 (m, 1H), 1.95-1.84 (m, 1H), 1.69-1.59 (m, 1H), 1.56 (d, J=7.2Hz, 3H), 1.54-1.45 (m, 2H), 1.44-1.28 (m, 2H), 1.19 (dq, J=12.3, 9.1 Hz,1H), 1.09 (d, J=6.4 Hz, 3H), 0.92 (ddt, J=12.5, 10.0, 8.5 Hz, 1H). IR(thin film) 2951, 2868, 1733, 1581, 1514, 1480, 1454, 1377, 1342, 1274,1249, 1211, 1131, 1095, 992, 913, 860, 801, 736, 703 cm⁻¹. HRMS-ESI(m/z) [M+Na]+ calcd for C₂₄H₃₀N₂O₄SNa, 465.1818; found, 465.1830.

Step2: Preparation of (1R,2S)-1-cyclopentyl-1-phenylpropan-2-yl(3-acetoxy-4-methoxypyridine-2-carbonothioyl)-L-alaninate.

To a solution of (1R,2S)-1-cyclopentyl-1-phenylpropan-2-yl(3-hydroxy-4-methoxypyridine-2-carbonothioyl)-L-alaninate (55 mg, 0.124mmol) dissolved in pyridine (1 mL, 0.124 mmol) was added aceticanhydride (0.25 mL, 0.124 mmol). After stirring for 1 hr at roomtemperature, the mixture was concentrated in vacuo and purified viaautomated column chromatography (0-50% acetone/hexanes as the eluent) tofurnish (1R,2S)-1-cyclopentyl-1-phenylpropan-2-yl(3-acetoxy-4-methoxypyridine-2-carbonothioyl)-L-alaninate (34 mg, 0.060mmol, 48.0% yield) as a brown oil. ¹H NMR (500 MHz, CDCl₃) δ 9.98 (d,J=7.3 Hz, 1H), 8.35 (d, J=5.4 Hz, 1H), 7.25-7.13 (m, 5H), 7.01 (d, J=5.5Hz, 1H), 5.39 (qd, J=6.3, 4.1 Hz, 1H), 5.16 (p, J=7.2 Hz, 1H), 3.91 (s,3H), 2.42 (dd, J=10.3, 4.0 Hz, 1H), 2.35 (s, 3H), 2.28-2.19 (m, 1H),1.93-1.83 (m, 1H), 1.68-1.59 (m, 1H), 1.52 (d, J=7.2 Hz, 3H), 1.50-1.31(m, 4H), 1.20 (dq, J=12.5, 9.1 Hz, 1H), 1.08 (d, J=6.4 Hz, 3H),0.97-0.90 (m, 1H). IR (thin film) 2950, 2868, 1770, 1731, 1585, 1496,1438, 1365, 1311, 1278, 1193, 1175, 1131, 1102, 1040, 1010, 909, 847,824, 759, 703 cm⁻¹. HRMS-ESI (m/z) [M+Na]+ calcd for C₂₆H₃₂N₂O₅SNa,507.1924; found, 507.1920.

Example 13: Preparation of2-(((S)-1-(((2S,3R)-3-(2,4-dimethylphenyl)-4-methylpentan-2-yl)oxy)-1-oxopropan-2-yl)carbamoyl)-3-hydroxy-4-ethoxypyridine 1-oxide

To a 25 mL vial charged with(2S,3R)-3-(2,4-dimethylphenyl)-4-methylpentan-2-yl(3-hydroxy-4-methoxypicolinoyl)-L-alaninate (38 mg, 0.089 mmol)dissolved in CH₂Cl₂ (1182 μL) was added 3-chlorobenzoperoxoic acid(mCPBA, 43.7 mg, 0.177 mmol) at room temperature. After stirringovernight, the reaction mixture was concentrated in vacuo and purifiedvia automated silica gel chromatography (0-50% acetone/hexanes as theeluent) to afford2-(((S)-1-(((2S,3R)-3-(2,4-dimethylphenyl)-4-methylpentan-2-yl)oxy)-1-oxopropan-2-yl)carbamoyl)-3-hydroxy-4-methoxypyridine 1-oxide (27 mg, 0.055 mmol,61.6% yield) as colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 14.37 (s, 1H),12.78 (d, J=7.0 Hz, 1H), 7.88 (d, J=7.1 Hz, 1H), 7.15 (d, J=7.7 Hz, 1H),6.90 (d, J=8.0 Hz, 2H), 6.77 (d, J=7.2 Hz, 1H), 5.42 (qd, J=6.3, 5.0 Hz,1H), 4.69-4.61 (m, 1H), 3.96 (s, 3H), 2.69 (dd, J=9.1, 5.0 Hz, 1H), 2.25(s, 3H), 2.23 (s, 3H), 2.00 (dp, J=8.8, 6.6 Hz, 1H), 1.44 (d, J=7.2 Hz,3H), 1.08 (d, J=6.3 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.69 (d, J=6.8 Hz,3H). IR (thin film) 2964, 1734, 1644, 1571, 1480, 1302, 1216 cm⁻¹.HRMS-ESI (m/z) [M+H]+ calcd for C₂₄H₃₃N₂O₆, 445.2333; found, 445.2370.

Example 14: Preparation of(2S,3R)-3-(2,4-dimethylphenyl)-4-methylpentan-2-yl(S)-2-(8-methoxy-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazin-3(4H)-yl)propanoate

To a 20 mL vial charged with(2S,3R)-3-(2,4-dimethylphenyl)-4-methylpentan-2-yl(3-hydroxy-4-methoxypicolinoyl)-L-alaninate (30 mg, 0.070 mmol) andtriphosgene (41.5 mg, 0.140 mmol) dissolved in CH₂Cl₂ (0.75 mL) wasadded pyridine (0.1 mL, 1.236 mmol) at room temperature. After stirringfor 45 min at room temperature, the crude LCMS revealed a completeconversion to the desired mass. The reaction mixture was quenched by theaddition of a saturated NaHCO₃ solution and was extracted with EtOAc(3×10 mL). The combined organic layers were washed with brine (10 mL).The organic solution was dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified via automated silica gel chromatography(0-40% acetone/hexanes as the eluent) to afford(2S,3R)-3-(2,4-dimethylphenyl)-4-methylpentan-2-yl(S)-2-(8-methoxy-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazin-3(4H)-yl)propanoate(28 mg, 0.059 mmol, 84% yield) as orange oil. ¹H NMR (500 MHz, CDCl₃) δ8.62 (d, J=5.3 Hz, 1H), 7.15 (d, J=5.4 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H),6.87-6.83 (m, 1H), 6.32-6.24 (m, 1H), 5.65 (q, J=7.1 Hz, 1H), 5.43 (qd,J=6.4, 3.2 Hz, 1H), 4.05 (s, 3H), 2.53 (dd, J=10.4, 3.2 Hz, 1H), 2.18(s, 3H), 2.10 (s, 3H), 2.06-1.96 (m, 1H), 1.71 (d, J=7.0 Hz, 3H), 1.04(d, J=6.5 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.60 (d, J=6.6 Hz, 3H). IR(thin film) 2958, 1770, 1715, 1371, 1244, 734 cm⁻¹. HRMS-ESI (m/z)[M+H]+ calcd for C₂₅H₃₁N₂O₆, 455.2177; found, 455.2171.

Example A: Evaluation of Fungicidal Activity: Leaf Blotch of Wheat(Zymoseptoria tritici; Bayer Code SEPTTR)

Technical grades of materials were dissolved in acetone, which were thenmixed with nine volumes of water containing 110 ppm Triton X-100. Thefungicide solutions were applied onto wheat seedlings using an automatedbooth sprayer to run-off. All sprayed plants were allowed to air dryprior to further handling. All fungicides were evaluated using theaforementioned method for their activity vs. all target diseases, unlessstated otherwise. Wheat leaf blotch and brown rust activity were alsoevaluated using track spray applications, in which case the fungicideswere formulated as EC formulations, containing 0.1% Trycol 5941 in thespray solutions.

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated withan aqueous spore suspension of Zymoseptoria tritici either prior to orafter fungicide treatments. After inoculation the plants were kept in100% relative humidity (one day in a dark dew chamber followed by two tothree days in a lighted dew chamber at 20° C.) to permit spores togerminate and infect the leaf. The plants were then transferred to agreenhouse set at 20° C. for disease to develop. When disease symptomswere fully expressed on the 1^(st) leaves of untreated plants, infectionlevels were assessed on a scale of 0 to 100 percent disease severity.Percent disease control was calculated using the ratio of diseaseseverity on treated plants relative to untreated plants.

Example B: Evaluation of Fungicidal Activity: Wheat Brown Rust (Pucciniatriticina; Synonym: Puccinia recondita f. sp. tritici; Bayer CodePUCCRT)

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated withan aqueous spore suspension of Puccinia triticina either prior to orafter fungicide treatments. After inoculation the plants were kept in adark dew room at 22° C. with 100% relative humidity overnight to permitspores to germinate and infect the leaf. The plants were thentransferred to a greenhouse set at 24° C. for disease to develop.Fungicide formulation, application and disease assessment followed theprocedures as described in the Example A.

Example C: Evaluation of Fungicidal Activity: Asian Soybean Rust(Phakopsora pachyrhizi; Bayer Code PHAKPA)

Technical grades of materials were dissolved in acetone, which were thenmixed with nine volumes of water containing 0.011% Tween 20. Thefungicide solutions were applied onto soybean seedlings using anautomated booth sprayer to run-off. All sprayed plants were allowed toair dry prior to further handling.

Soybean plants (variety Williams 82) were grown in soil-less Metro mix,with one plant per pot. Two week old seedlings were used for testing.Plants were inoculated either 3 days prior to or 1 day after fungicidetreatments. Plants were incubated for 24 h in a dark dew room at 22° C.and 100% relative humidity then transferred to a growth room at 23° C.for disease to develop. Disease severity was assessed on the sprayedleaves.

Example D: Evaluation of Fungicidal Activity: Tomato Early Blight(Alternaria solani; Bayer Code ALTESO)

Tomato plants (variety Outdoor Girl) were propagated in soil-less Metromix, with each pot having one plant, and used when 12 to 14 days old.Test plants were inoculated with an aqueous spore suspension ofAlternaria solani 24 hr after fungicide treatments. After inoculationthe plants were kept in 100% relative humidity (one day in a dark dewchamber followed by two to three days in a lighted dew chamber at 20°C.). to permit spores to germinate and infect the leaf. The plants werethen transferred to a growth room at 22° C. for disease to develop.Fungicide formulation, application and disease assessment on the sprayedleaves followed the procedures as described in the Example A.

Example E: Evaluation of Fungicidal Activity: Leaf Spot of Sugar Beets(Cercospora beticola; Bayer Code CERCBE)

Sugar beet plants (variety HH88) were grown in soil-less Metro mix andtrimmed regularly to maintain a uniform plant size prior to test. Plantswere inoculated with a spore suspension 24 hr after fungicidetreatments. Inoculated plants were kept in a dew chamber at 22° C. for48 hr then incubated in a greenhouse set at 24° C. under a clear plastichood with bottom ventilation until disease symptoms were fullyexpressed. Fungicide formulation, application and disease assessment onthe sprayed leaves followed the procedures as described in the ExampleA.

Example F: Evaluation of Fungicidal Activity: Cucumber Anthracnose(Glomerella lagenarium; Anamorph: Colletotrichum lagenarium; Bayer CodeCOLLLA)

Cucumber seedlings (variety Bush Pickle) were propagated in soil-lessMetro mix, with each pot having one plant, and used in the test when 12to 14 days old. Test plants were inoculated with an aqueous sporesuspension of Colletotrichum lagenarium 24 hr after fungicidetreatments. After inoculation the plants were kept in a dew room at 22°C. with 100% relative humidity for 48 hr to permit spores to germinateand infect the leaf. The plants were then transferred to a growth roomset at 22° C. for disease to develop. Fungicide formulation, applicationand disease assessment on the sprayed leaves followed the procedures asdescribed in the Example A.

Example G: Evaluation of Fungicidal Activity: Wheat Glume Blotch(Parastagonospora nodorum; Bayer Code LEPTNO)

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated withan aqueous spore suspension of Parastagonospora nodorum 24 hr afterfungicide treatments. After inoculation the plants were kept in 100%relative humidity (one day in a dark dew chamber followed by two days ina lighted dew chamber at 20° C.) to permit spores to germinate andinfect the leaf. The plants were then transferred to a greenhouse set at20° C. for disease to develop. Fungicide formulation, application anddisease assessment followed the procedures as described in the ExampleA.

Example H: Evaluation of Fungicidal Activity: Cucumber Downy Mildew(Pseudoperonospora cubensis; Bayer Code PSPECU)

Cucumber seedlings (variety Bush Pickle) were grown in soil-less Metromix, with one plant per pot, and used in the test when 12 to 14 daysold. Plants were inoculated with a spore suspension 24 hr followingfungicide treatments. Test plants were inoculated with an aqueous sporesuspension of Pseudoperonospora cubensis 24 hr after fungicidetreatments. After inoculation the plants were kept in a dew room at 22°C. with 100% relative humidity for 24 hr to permit spores to germinateand infect the leaf. The plants were then transferred to a greenhouseset at 20° C. until disease was fully expressed. Fungicide formulation,application and disease assessment on the sprayed leaves followed theprocedures as described in the Example A.

Example I: Evaluation of Fungicidal Activity: Rice Blast (Magnaporthegrisea; Anamorph: Pyricularia oryzae; Bayer Code PYRIOR)

Rice seedlings (variety Japonica) were propagated in soil-less Metromix, with each pot having 8 to 14 plants, and used in the test when 12to 14 days old. Test plants were inoculated with an aqueous sporesuspension of Pyricularia oryzae 24 hr after fungicide treatments. Afterinoculation, the plants were kept in a dew room at 22° C. with 100%relative humidity for 48 hr to permit spores to germinate and infect theleaf. The plants were then transferred to a greenhouse set at 24° C. fordisease to develop. Fungicide formulation, application and diseaseassessment on the sprayed leaves followed the procedures as described inthe Example A.

Example J: Evaluation of Fungicidal Activity: Barley Scald(Rhyncosporium secalis; Bayer Code RHYNSE)

Barley seedlings (variety Harrington) were propagated in soil-less Metromix, with each pot having 8 to 12 plants, and used in the test whenfirst leaf was fully emerged. Test plants were inoculated by an aqueousspore suspension of Rhyncosporium secalis 24 hr after fungicidetreatments. After inoculation the plants were kept in a dew room at 20°C. with 100% relative humidity for 48 hr. The plants were thentransferred to a greenhouse set at 20° C. for disease to develop.Fungicide formulation, application and disease assessment on the sprayedleaves followed the procedures as described in the Example A.

Example K: Evaluation of Fungicidal Activity: Grape Powdery Mildew(Uncinula necator; Bayer Code UNCINE)

Grape seedlings (variety Carignane) were grown in soil-less Metro mix,with one plant per pot, and used in the test when approximately 1 monthold. Plants were inoculated 24 hr after fungicide treatment by shakingspores from infected leaves over test plants. Plants were maintained ina greenhouse set at 20° C. until disease was fully developed. Fungicideformulation, application and disease assessment on sprayed leavesfollowed the procedures as described in the Example A.

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LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20180186743A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

What is claimed is:
 1. A composition for the control of a fungalpathogen including mixtures of at least one of the compounds of FormulaI

wherein: X is hydrogen or C(O)R₅; Y is hydrogen, C(O)R_(5,) or Q; Q is

wherein Z is N or N⁺→O⁻ and W is O or S; R₁ is hydrogen or alkyl,substituted with 0,1 or multiple R₈; R₂ is methyl; R₃ and R₃′ areindependently chosen from C₂-C₆ alkyl, C₃-C₆ cycloalkyl, aryl orheteroaryl, each optionally substituted with 0, 1 or multiple R₈;Alternatively, R₃ and R₃′ may be taken together to form a 3-6 memberedsaturated or partially saturated carbocycle or heterocycle, optionallysubstituted with 0, 1 or multiple R₈; R₄ is chosen from aryl orheteroaryl, each optionally substituted with 0, 1 or multiple R₈; R₅ ischosen from alkoxy or benzyloxy, each optionally substituted with 0, 1,or multiple R₈; R₆ is chosen from hydrogen, alkoxy, or halo, eachoptionally substituted with 0,1, or multiple R₈; R₇ is chosen fromhydrogen, —C(O)R₉, or —CH₂OC(O)R₉; R₈ is chosen from hydrogen, alkyl,aryl, acyl, halo, alkenyl, alkynyl, alkoxy, cyano, or heterocyclyl, eachoptionally substituted with 0, 1, or multiple R_(10;) R₉ is chosen fromalkyl, alkoxy, or aryl, each optionally substituted with 0, 1, ormultiple R₈; R₁₀ is chosen from hydrogen, alkyl, aryl, acyl, halo,alkenyl, alkoxy, or heterocyclyl; R₁₁ is chosen from hydrogen or alkyl,each substituted with 0, 1 or multiple R₈; and a phytologicallyacceptible carrier material.
 2. The composition according to claim 1,wherein X is hydrogen and Y is Q.
 3. The composition according to claim2 wherein Z is N.
 4. The composition according to claim 3 wherein W isO.
 5. The composition according to claim 4, wherein R₆ is alkoxy.
 6. Thecomposition according to claim 5, wherein R₇ is hydrogen.
 7. Thecomposition according to claim 6, wherein R₁ and R₁₁ are independentlychosen from hydrogen or alkyl, R₃ and R₃′ are independently chosen fromC₂-C₆ alkyl or taken together to form a 3-6 membered saturatedcarbocycle, each optionally substituted with 0, 1 or multiple R₈, and R₄is aryl, optionally substituted with 0, 1 or multiple R₈.
 8. Thecomposition according to claim 5, wherein R₇ is chosen from —C(O)R₉, or—CH₂OC(O)R₉.
 9. The composition according to claim 8, wherein R₉ isalkyl, optionally substituted with 0, 1 or multiple R₈.
 10. Thecomposition according to claim 9, wherein R₁ and R₁₁ are independentlychosen from hydrogen or alkyl, R₃ and R₃′ are independently chosen fromC₂-C₆ alkyl or taken together to form a 3-6 membered saturatedcarbocycle, each optionally substituted with 0, 1 or multiple R₈, and R₄is aryl, optionally substituted with 0, 1 or multiple R₈.
 11. Thecomposition according to claim 1 wherein the fungal pathogen is one ofLeaf Blotch of Wheat (Zymoseptoria tritici), Wheat Brown Rust (Pucciniatriticina), Stripe Rust (Puccinia striiformis), Scab of Apple (Venturiainaequalis), Blister Smut of Maize (Ustilago maydis), Powdery Mildew ofGrapevine (Uncinula necator), Barley scald (Rhynchosporium secalis),Blast of Rice (Pyricularia oryzae), Rust of Soybean (Phakopsorapachyrhizi), Glume Blotch of Wheat (Parastagonospora nodorum), PowderyMildew of Wheat (Blumeria graminis f. sp. tritici), Powdery Mildew ofBarley (Blumeria graminis f. sp. hordei), Powdery Mildew of Cucurbits(Erysiphe cichoracearum), Anthracnose of Cucurbits (Colletotrichumlagenarium), Leaf Spot of Beet (Cercospora beticola), Early Blight ofTomato (Alternaria solani), and Net Blotch of Barley (Pyrenophorateres).
 12. The composition according to claim 7 wherein the fungalpathogen is one of Leaf Blotch of Wheat (Zymoseptoria tritici), WheatBrown Rust (Puccinia triticina), Scab of Apple (Venturia inaequalis),Barley scald (Rhynchosporium secalis), Blast of Rice (Pyriculariaoryzae), Rust of Soybean (Phakopsora pachyrhizi), Glume Blotch of Wheat(Parastagonospora nodorum), Anthracnose of Cucurbits (Colletotrichumlagenarium), Leaf Spot of Beet (Cercospora beticola), and Early Blightof Tomato (Alternaria solani).
 13. The composition according to claim 8wherein the fungal pathogen is one of Leaf Blotch of Wheat (Zymoseptoriatritici), Wheat Brown Rust (Puccinia triticina), Scab of Apple (Venturiainaequalis), Barley scald (Rhynchosporium secalis), Blast of Rice(Pyricularia oryzae), Rust of Soybean (Phakopsora pachyrhizi), GlumeBlotch of Wheat (Parastagonospora nodorum), Anthracnose of Cucurbits(Colletotrichum lagenarium), Leaf Spot of Beet (Cercospora beticola),and Early Blight of Tomato (Alternaria solani).
 14. The compositionaccording to claim 10 wherein the fungal pathogen is one of Leaf Blotchof Wheat (Zymoseptoria tritici), Wheat Brown Rust (Puccinia triticina),Scab of Apple (Venturia inaequalis), Barley scald (Rhynchosporiumsecalis), Blast of Rice (Pyricularia oryzae), Rust of Soybean(Phakopsora pachyrhizi), Glume Blotch of Wheat (Parastagonosporanodorum), Anthracnose of Cucurbits (Colletotrichum lagenarium), LeafSpot of Beet (Cercospora beticola), and Early Blight of Tomato(Alternaria solani).
 15. A method for the control and prevention offungal attack on a plant, the method including the step of: applying afungicidally effective amount of at least one of the compositions ofclaim 7 to at least one of the plant, an area adjacent to the plant,soil adapted to support growth of the plant, a root of the plant, andfoliage of the plant
 16. A method for the control and prevention offungal attack on a plant, the method including the step of: applying afungicidally effective amount of at least one of the compositions ofclaim 10 to at least one of the plant, an area adjacent to the plant,soil adapted to support growth of the plant, a root of the plant, andfoliage of the plant
 17. A method for the control and prevention offungal attack on a plant, the method including the step of: applying afungicidally effective amount of at least one of the compositions ofclaim 11 to at least one of the plant, an area adjacent to the plant,soil adapted to support growth of the plant, a root of the plant, andfoliage of the plant.
 18. A method for the control and prevention offungal attack on a plant, the method including the step of: applying afungicidally effective amount of at least one of the compositions ofclaim 14 to at least one of the plant, an area adjacent to the plant,soil adapted to support growth of the plant, a root of the plant, andfoliage of the plant.